Week 6.

Viral Hepatitides.

1. Describe the different viruses responsible for viral hepatitides, with special emphasis on differentiating those that are
enterically transmitted from those that are parenterally transmitted and discuss the consequences thereof (self-limited
disease versus chronic disease, epidemiology etc.).
Hepatitis viruses A,B,C,D, and E account for > 95% of viral hepatitis (inflammation of the liver); although all five can
cause acute hepatitis, only HBV, HCV, and HDV result in chronic hepatitis.
~ HAV and HEV are transmitted enterically; HBV, HCV, and HDV are transmitted parenterally.
2. Briefly describe and discuss the clinical features of viral hepatitides.
ACUTE Viral Hepatitis CHRONIC Viral Hepatitis
Clinical presentation: variable systemic prodromal symptoms Ranges from asymptomatic to end-stage fatal hepatic
(1-2 wks) include headache, myalgias, arthralgias, fatigue, failure  fatigure, persistent or intermittent jaundice,
weakness, anorexia, nausea, vomiting, cough, pharyngitis, malaise, anorexia.
photophobia, coryza, low-grade fever (esp. in HAV), ↑ ALT & * Failure to recover within 6 months of disease onset
AST, RUQ discomfort, epigastric discomfort, hepatomegaly, indicates chronic hepatitis.
splenomegaly, alteration of taste & smell. - HBV is likely to become chronic in children & elderly;
* While systemic symptoms subside, there is (1) dark urine – HCV infection leads to chronicity in majority of cases.
bilirubin, (2) mildly elevated ALP, (3) acholic (pale or clay- * Long-term complications: cirrhosis, decompensated
colored) stools, (4) jaundice. liver disease, hepatocellular carcinoma (HCC).
HAV, HEV – complete recovery expected 1-2 mo after onset. - HDV and HIV co-infection w/ HBV ↑ risk of cirrhosis.
HBV – complete recovery expected 3-6 mo after onset. - HCV and HIV co-infection ↑ risk of liver fibrosis.
HCV – complete recovery in less than half the time.
Diagnosis of viral hepatitis:
ACUTE Infection CHRONIC Infection
VIRUS Pattern Interpretation Pattern Interpretation
HAV Anti-HAV IgM Acute HAV infection Never cause chronic infections.
HEV Serologic exclusion of all other viral hepatitis
causing agents.
HBV HBsAg & anti-HBc IgM Acute HBV infection HBsAg & anti-HBc IgG Chronic HBV infection
HDV HBsAg & anti-HDV IgM Acute HDV infection HBsAG & anti-HDV IgG Chronic HDV infection
HCV Anti-HCV IgM Acute HCV infection Anti-HCV IgG Chronic HCV infection
3. Describe the epidemiological settings associated with infection and discuss the consequences thereof (e. g. acquisition
of HBV at birth as opposed to adulthood, co-infections etc.). 4. Describe the replicative cycles of representative viruses
responsible for viral hepatitides (HAV, HBV, HCV & HDV) and discuss how these relate to disease.
VIRUS FEATURES EPIDEMIOLOGY DISEASE PREVENTION
I. Enterically transmitted hepatitis.
Hepatitis Picornaviridae Worldwide; transmitted mostly via Incubation period 28 days (ranges 2 Preventable
A Virus - naked (+) fecal-oral route – viruses survive -7 wks); generally no cytopathic by vaccine
ssRNA; days – weeks in environment & effect from the virus - hepatocyte (formalin-
icosahedral; resist GI pH. damage induced by immune inactivated
limited range ~ In endemic regions, HAV infection is mechanisms (CD8-mediated). whole virus).
of hosts nearly universal in children & clinically
(primates). unapparent (disease severity ↑ w/ age); * HAV
in developed countries, HAV infection is infection
predominately seen in travelers most likely
returning from endemic regions. provides
Risk factors: (1) poor socio- lifelong
economic conditions – immunity;
overcrowding, poor hygiene & serum IgG
sanitation, (2) high-risk behaviors & (against VP1 /
~ regeneration + normalization of
occupations: oral-anal contact, IV
liver functions usually within 8 - 12 VP3 epitope)
 drug use, consumption of raw / wks. sufficient to
inadequately cooked food (esp. Complications: fulminant hepatitis protect
shellfish) & water in endemic areas, (acute liver failure) – can occur in against
(3) institutional workers, (4) pts w/ children, but more common & infection.
chronic liver disease. severe in pts > 50 yo; survivors
* can be transmitted by blood! recover complete liver function.
Hepatitis Hepeviridae – Worldwide; transmitted mostly via No antiviral
E Virus naked (+) fecal-oral route (contaminated therapy or
ssRNA; water); viruses resist GI pH. vaccine.
icosahedral; ~ background level of sporadic HEV
wide genetic infections in endemic areas
variation but accompanied by major outbreaks every
only one 7 - 10 yrs (epidemics assoc. w/ “wet
season”.
serotype; host
~ in developed countries, HEV infection
range includes seen in travelers returning from
swine & endemic regions & people in close
primates. contact with pigs (swine strains).
II. Parenterally transmitted hepatitis.
Hepatitis Hepadnavirus Worldwide; transmitted perinatally & Incubation 60-180 days; clinical Immunity:
B Virus – enveloped, via bodily fluids (all ages); resistant presentation ranges from CD4, CD8, NK
gapped viruses able to survive outside host for asymptomatic to liver failure. cells, antiviral
circular at least a week. * Except for highly particular cases state (IFN-α,
dsDNA; 4 ~ In countries w/ low HBV (e.g. overexpression of viral L-protein), TNF-α),
prevalence, sexual activity is the immunization
serotypes, generally no cytopathic effect from
most likely mode of transmission. provides cross-
narrow host the virus; hepatocyte damage protection
range (related ~ In countries w/ high prevalence, induced by immune mechanisms. across all
primates). perinatal infection in the most likely - regeneration + normalization of serotypes
Antigens: mode of transmission. liver functions within 8-12 wks. (anti-HBsAg)
HBsAg – Risk factors: IV drug users, Complications: fulminant hepatitis  long-lasting
surface household contacts, sexual partners (most common form). immunity.
glycoprotein of carriers, multiple sexual partners, Mechanisms of chronicity: (1) Dx: ELISA,
in envelope. healthcare workers (needle-stick), immune status, (2) tolerization: PCR.
HBcAg – core multiple blood transfusions or HBsAg, HBeAg, (3) modulation of Prevention:
(or capsid) hemodialysis. antiviral state, (4) modulation of passive
protein. * initial age of infection & immune cell-mediated immunity: ↓ non- immuno-
status also play a role. prophylaxis for
HBeAg – cytolytic CD8 cells, Treg,
exposed
peptide from interference w/ Ag presentation neonates,
viral mechanisms. healthcare
replication. workers;
* See below for hepatocellular carcinoma. vaccines.

Hepatitis Deltaviridae - Worldwide, transmitted - HDV/HBV co-infection ↑the Same as HBV.

D Virus Enveloped, parenterally, sexually; co-habitation likelihood of cirrhosis, assoc. w/
defective (-) w/ HDV-positive individuals is higher mortality rates than HBV
ssRNA virus; considered a major risk factor. infections alone.
relies on HBV - in the setting of superinfection,
for replication; fulminant hepatitis & chronic
only one hepatitis tend to be more severe.
serotype, host
range same as
HBV.
Hepatitis Flaviviridae - Worldwide; infection undetectable Incubation 6-8 ks; clinical Immunity:
C Virus Enveloped (+) in children <15, increases in presentation typically cell-
ssRNA; 6 individuals >15 (pathogenesis = asymptomatic or mild; severe acute mediated,
major function of age). hepatitis is rare. humoral.
genotypes (1- - lack of immunity  re-infections. ~ steatosis is a typical feature of Re-infections
3 most - transmitted via blood, blood chronic HCV infection. occur, so
important) & products, vertically & perinatally. ~ cirrhosis is found in 20% cases, immunity is
3 subtypes (a, - acute HCV hepatitis superimposed on 20-25 % of which progress to HCC. not long-
b, c); very pre-existing liver disease may accelerate ~ time from initial infection to HCC lasting.
narrow host liver decompensation and death! 10 to 50 yrs and invariably Dx: ELISA,
range - HCV-HBV co-infection is common, involves cirrhosis. recombinant
(humans & more severe, progresses to HCC more immunoblot
chimpanzees). often & is likely to be more refractory to assay (RIBA),
IFN- treatment. RT-PCR.
- HCV inhibits HBV (HBV infection may Prevention:
be occult when measured by standard behavior
serological tests) - HBV PCR testing
modification,
recommended for chronic HCV patients.
passive
~ In developed countries, HCV is the
immuno-
major cause of chronic viral hepatitis
prophylaxis.
(main cause of cirrhosis in US). Mechanisms of chronicity: (1)
~ Fast fibrosers will reach cirrhosis modulation of antiviral state, (2)
within 20 yrs, slow fibrosers will modulation of cell-mediated
reach it after > 50 yrs. immunity (Treg).
Risk groups: IV drug users, pts
receiving multiple transfusions or
hemodialysis, healthcare workers.
5. Describe the immune responses to viral hepatitides and discuss how these contribute to viral clearance or
persistence. 6. Describe and discuss viral immune response subversion mechanisms and how these contribute to
disease. 7. Describe the immunopathogenesis of viral hepatitides. See above.
8. Describe HBV and HCV oncogenesis.
HBV & Hepatocellular Carcinoma: continual chronic infection leads to ↑ hepatocyte proliferation to compensate for
destruction caused by virus + immune response  increased probability of DNA mutations over time.
~ free radical production by immune effector cells presumably ↑likelihood of hepatocyte DNA damage & mutagenesis.
~ HBV X protein activates transcription of various cellular genes, including proto-oncogenes.
9. Describe the laboratory diagnostic methods used for hepatitide detection and interpret the serology and viral load
results associated with the diagnosis of viral hepatitides, as well as how these relate to viral replication and disease
progression. 10. Describe the mechanisms of action of treatments associated with parenterally transmitted hepatitis
viruses (especially IFN- and nucleoside analogs). 11. Describe prevention methods for viral hepatitides (vaccination,
hygiene etc.). See above.

Other causes of viral hepatitis: ALL human herpesviruses (especially EBV), some hemorrhagic fever viruses, certain
adenoviruses, certain enteroviruses.
Pathology of Non-neoplastic Liver Diseases.

Acute Hepatitis Fulminant Hepatitis Chronic Hepatitis

Subclinical infections identified (incidentally)
by mildly elevated liver enzymes or detection
of antiviral Abs.
Symptomatic infections assoc. w/ fatigue, loss
of appetite, & jaundice.
Progression from onset of
symptoms to hepatic failure in
2- 3 wks; mortality is high (up
to 80% w/o liver
transplantation).
~ can be viral (hepatitis B or A)
or caused by drug toxicity (e.g.
acetominophen overdose).
Morphology: small shunken
liver with extensive necrosis.
Symptomatic, biochemical or
serologic evidence of continuing /
relapsing hepatic disease w/
histologic documentation (> 6 mo).
Young age at time of infection ↑ risk
of chronicity; Hepatitis C most
common cause of chronic viral
hepatitis.

Morphology:
- swollen hepatocytes (ballooning
degeneration) & dead hepatocytes (acidophilic Morphology: continued inflammation
bodies). & hepatocyte damage (same as acute
- cholestasis (blocked flow of bile from liver). hepatitis but generally milder) +
- Kupffer cell hyperplasia. fibrosis (determines stage).
- portal inflammation spilling into periportal ~ Hepatitis C  lymphoid
hepatocytes (piecemeal necrosis or interface aggregates, steatosis.
hepatitis). ~ Hepatitis B  “ground glass”
hepatocytes.

Autoimmune Hepatitis: clinically similar to viral hepatitis (usually chronic but can be fulminant) & often assoc. w/ other
autoimmune diseases (lupus, rheumatoid arthritis, etc) - autoantibodies present.
~ most common histology is chronic hepatitis with ↑ plasma cells; often leads to cirrhosis.
~ therapy includes immunosuppression.
 Drug-Induced Liver Disease: occurs in up to 40/100,000 pts; can be due to direct
toxicity, hepatic conversion of drug to toxin, or via immune mechanism.
~ may be predictable (toxic to anyone with sufficient dose) or idiosyncratic (dependent
on differences in host metabolism / immune reaction).
~ MAY MIMIC OR INDUCE ANY TYPE OF LIVER DISEASE (cholestasis, hepatitis, necrosis,
steatosis, steatohepatitis, fibrosis, granulomas, vascular lesions and tumors)
* Acetominophen overdose is most common cause of acute liver failure due to
massive necrosis.
Fatty Liver Disease is the most common liver disease in the U.S, characterized by 3 stages: (1) steatosis – reversible fatty
change, (2) steatohepatitis – liver cell injury +/- fibrosis, (3) cirrhosis – end stage fibrosis. Most common causes =
obesity, alcohol abuse.
Morphology of steatohepatitis: (1) hepatocyte
swelling & necrosis, (2) Mallory bodies (eosinophilic
cytoplasmic clumps of cytokeratin; also seen in
Wilson Disease, alpha-1 antitrypsin deficiency, etc),
(3) neutrophilic infiltrates, (4) pericellular fibrosis
(starts in central zone).

Hemochromatosis: autosomal recessive disease (Chr. 6 mutation) causing ↑ absorption of dietary iron (↓ hepcidin,
which blocks release of iron from intestinal cells)  iron accumulates in liver & pancreas, can cause cirrhosis and
diabetes mellitus.
~ differentiate from acquired iron overload (hemosiderosis) due to ineffective erythropoiesis, transfusions, etc.
Morphology: hemosiderin deposits in hepatocytes & bile ducts, fibrosis (eventually cirrhosis), direct hepatotoxicity from
iron, usually NO inflammation. Tx: phlebotomy.
Wilson Disease: autosomal recessive disease (ATP7B gene mutation) characterized by impaired excretion of copper into
bile (failure to incorporate copper into ceruloplasmin)  toxic levels accumulate in liver, eyes (Kayser-Fleisher rings) &
brain; liver can show steatosis, acute or chronic hepatitis, massive necrosis or cirrhosis.
Dx: excess hepatic copper can be demonstrated with special stains (nonspecific ↑ w/ cholestasis); ↓serum
ceruloplasmin, ↑ quantitative hepatic copper & urinary copper more helpful.
Alpha-1 Antitrypsin (A1AT) Deficiency: autosomal recessive disorder (abnormal SERPINA1 gene on Chr. 14) - A1AT is
abnormally formed & accumulates in liver endoplasmic reticulum (not secreted) causing liver cell damage; low systemic
A1AT leads to pulmonary emphysema due to uninhibited inflammatory proteases.
~ liver A1AT accumulations appear as PAS + cytoplasmic globules; may be assoc. w/ cholestatic hepatitis or cirrhosis.
~ A1AT globules in the liver not entirely specific; genotyping & serotyping helpful in Dx.
Condition Etiology Morphology Clinical Features
Primary Biliary Evidence for Non-suppurative, often granulomatous, Insidious onset (usually w/
Cirrhosis - chronic autoimmunity; destruction of medium-sized intrahepatic bile pruritis), jaundice late in
progressive (often >90% have anti- ducts (florid duct lesion). course, hepatomegaly &
fatal) disease mitochondrial - cholestasis & cirrhosis (eventually) develop. xanthomas, hepatic
characterized by antibodies. decompensation.
destruction of ~ causes of death: liver
intrahepatic bile failure, massive variceal
ducts, inflammation bleed, intercurrent
& scarring. infection.
Tx: Ursodeoxycholic acid
(early), liver transplant
(late).
Secondary Biliary Biliary atresia, Bile stasis, bile ductular proliferation, fibrosis Non-specific signs of
Cirrhosis – arises gallstones, /cirrhosis. If accompanied by infection, obstruction (jaundice,
from prolonged stricture, neutrophils are seen in bile ducts (ascending secondary infection).
obstruction of extra- carcinoma of cholangitis).
hepatic biliary tree. pancreatic head.
Primary Sclerosing Seen in 3rd – 5th ~ segmental constriction of ducts gives
Cholangitis – decade; assoc. beaded appearance to biliary tree on
characterized by w/ ulcerative cholangiogram.
inflammation & colitis. ~ fibrosing lymphocytic inflammation of bile
fibrosis that ~ increases risk ducts - concentric “onion skin” fibrosis.
obliterates intra- & for cholangio- ~ eventual areas of fibrous obliteration w/
extrahepatic bile carcinoma. intervening duct dilatation.
ducts. ~ liver shows marked cholestasis & eventually
biliary cirrhosis.
Cirrhosis – end stage Architecture of entire liver disrupted & Mechanisms of death from
chronic liver disease. transformed to fibrosis w/ regenerative cirrhosis include liver
nodules. Core events: hepatocellular death  failure, portal hypertension,
fibrosis (type I & III collagen deposited by & hepatocellular carcinoma.
stellate cells in space of Disse), vascular Complications: (1) hepatic
reorganization  hepatocytes stimulated to encephalopathy (assoc. w/ ↑
regenerate as spherical nodules  ammonia in blood & CNS 
inadequate blood supply. behavioral abnormalities,
- micronodular, macronodular. stupor, coma, etc, (2)
hepatorenal syndrome w/ ↓
renal perfusion, activation of
renal sympathetic system, ↑
synthesis of vasoactive
mediators, (3)
hepatopulmonary syndrome
as result of liver failure –
hypoxemia due to ventilation-
perfusion mismatch, mediated
by ↑ NO.
*Portal Hypertension: cirrhosis causes ↑ resistance to portal blood flow, shunts develop where there are anatomoses
between portal & systemic circulation  esophageal varices, splenomegaly, caput medusae, ascites & jaundice, spider
angiomas,
Esophageal Varices: varicose veins in esophagus form @ anastomoses between portal & caval systems due to
prolonged or severe portal hypertension (generally from cirrhosis); often rupture causing serious hemorrhage (50%
fatal).
Hemorrhoids: variceal dilations of anal & perianal venous plexuses (internal or external) caused by chronic
constipation, pregnancy, liver cirrhosis. Complications: hemorrhages, ulceration, fissures, infarction.
* Hepatic Circulatory Disorders: circulation can be disrupted via (1) obstruction to inflow of blood – portal vein, hepatic
artery – infarcts rare due to dual blood supply, (2) compromise to sinusoidal blood flow – obstruction, systemic
hypoperfusion, (3) hepatic vein outflow obstruction - passive congestion, hepatic vein thrombosis, hepatic veno-
occlusive disease.
~ Passive congestion is commonly seen on autopsy and is assoc. w/ right
heart failure, elevated liver enzymes; congestion followed by necrosis /
fibrosis of centrilobular areas (zone 3)  grossly mottled, red (nutmeg
liver).

~ Budd-Chiari Syndrome: liver enlargement, pain & ascites due to

obstruction of two or more major hepatic veins; assoc. w/
myeloproliferative disorders, hypercoagulable states & cancers, esp.
heptocellular carcinoma  marked centrilobular congestion & necrosis,
often fatal without rapid surgical correction.

Pathology of Pancreas, Gallbladder, and Liver Tumors.

Cholelithiasis (gallstones) are often clinically silent; majority are cholesterol stones (yellow), others are from bilirubin
calcium salts (black). Risk factors: ↑ age, F gender, obesity, drugs which ↑cholesterol concentration in bile(oral
contraceptives, Clofibrate), conditions which ↑ bilirubin in bile (hemolytic syndromes, biliary infections).
Pathogenesis of cholesterol stones: ↑ cholesterol in bile exceeds capacity of bile acids & lecithins that keep it soluble 
supersaturated biliary cholesterol forms crystals which aggregate into stones; promoters include gallbladder
hypomotility & ↑ mucin secretion. Complications: acute abdomen due to cholecystitis, pancreatitis, biliary colic.
ACUTE Cholecystitis CHRONIC Cholecystitis
Acute inflammation of gallbladder; 90% cases arise from obstruction of May occur as a sequel to bouts of
gallbladder neck or cystic duct by stones (calculous cholecystitis)  increased acute cholecystitis or without clinical
intraluminal pressure, compromised blood flow to mucosa. evidence of previous disease (>90%
Obstruction distension   lumenal pressure  vascular compromise  associated with cholelithiasis) 
ischemia  inflammation ± bacteria. fibrosis, chronic inflammation, &
10% cases without stones (acalculous cholecystitis) may be due ischemia or mucosal diverticulae.
viscous bile causing functional obstruction - often develops in sick patients Complications: infection,
hospitalized for other conditions (direct ischemic compromise resulting from perforation/rupture + peritonitis,
sepsis, trauma, diabetes, post-partum & post-operative states). abscess, fistula.

~ assoc. w/ acute
inflammation / necrosis; may
be a medical emergency or
resolve without intervention.

Choledocholithiasis (stones in common bile duct) may lead to obstruction, pancreatitis, cholangitis (bile duct infection),
hepatic abscess, & secondary biliary cirrhosis.
I. ACUTE PANCREATITIS - 80% of cases caused either by alcohol or biliary tract disease; other causes include infection,
trauma, genetic, ischemia, metabolic conditions (hyperlipidemia, hypercalcemia) & certain medications (Furosemide,
estrogens)  acute onset of abdominal pain results from enzyme-induced necrosis & inflammation of pancreas &
adjacent fat.
~ hemorrhage, fat necrosis, proteolysis (see below).
 Alcohol & pancreatitis:
Alcohol leads to protein-rich
secretions which plug small
ducts, ↑ pancreatic secretion,
causes transient contraction of
the sphincter of Oddi & has a
direct toxic effect on acinar
cells.

Signs & Symptoms: abdominal

pain (mild to severe / acute
abdomen); typically pain is
constant, intense and refers to
back & shoulder.
- severity of symptoms due to release of
toxic enzymes, cytokines, etc.
Complications: leukocytosis,
hemolysis, DIC, fluid
sequestration, diffuse fat
necrosis, ARDS, shock, abscess,
pseudocysts, obstruction of
duodenum.
II. CHRONIC PANCREATITIS - caused by repeated bouts of mild to moderate acute pancreatitis  continued loss of
parenchymal cells  fibrosis (irreversible); may be due to alcohol abuse (most common), long-standing duct obstruction
(stones, tumors, malformations), idiopathic causes(inherited mutations  inappropriate activation of enzymes).
Morphology: fibrosis, chronic inflammation, acinar loss, proliferation of ductules & islets (can be mistaken for
neoplasm). Clinical: recurrent / persistent abdominal & back pain (intensity varies), stimulated by alcohol & overeating.
Complications: pancreatic insufficiency (steatorrhea, malabsorption), diabetes mellitus, pseudocysts, duct obstruction.

Tumors & Cysts of Exocrine Pancreas:

~ congenital pancreatic cysts arise from anomalous duct development – may be sporadic or assoc. w/ polycystic kidney
disease or von Hippel-Lindau disease; lined by cuboidal epithelium.
~ pancreatic pseudocysts are secondary to necrosis from pancreatitis or trauma (most common cystic lesion of
pancreas); fibrous lining, no epithelium.
Tumor Features Histology
Pancreatic Benign multicystic neoplasm w/ glycogen-rich clear
Serous cuboidal epithelium.
Cystadenoma - usually arises in 7th decade, F > M; 25% of pancreatic
cystic neoplasms.

Grapefruit?
Mucinous cystic neoplasms are found mainly in women, usually in the body or tail of pancreas; do NOT connect w/
major pancreatic ducts.
~ 2/3 benign (mucinous cystadenoma), 1/3 harbor invasive adenocarcinoma (mucinous cystadenocarcinoma); need
complete resection to rule out carcinoma.
~ may have cellular ovarian type stroma; mucous columnar epithelium.
Mucinous
Cystadenoma

Mucinous
Cystadeno-
carcinoma

Intraductal Dilatation of existing pancreatic ducts w/ dysplastic

Papillary mucinous epithelium (NO ovarian type stroma);
Mucinous usually centered in pancreatic head.
Neoplasm ~ precursor lesion to pancreatic adenocarcinoma.
~ excellent prognosis w/ resection if invasion has not
yet occurred.

Pancreatic 4th leading cause of cancer death in US – mostly seen

Carcinoma in the elderly; poor prognosis.
* smoking doubles risk, high fat diet & alcohol may
also contribute.
* risk much higher w/ family history for Peutz –
Jeghers syndrome (hereditary intestinal polyposis).
- precursor lesions = “pancreatic intraepithelial
neoplasias” (PanIN).
- 60% arise in head, 15% in body, 5% in tail; 20% affect
entire gland; most are clinically silent until disease is
advanced.
Carcinoma of the head may present w/ obstructive
jaundice; metastasis to regional nodes & liver as well
as peritoneum, lungs, adrenals & bones may occur;
extension to neighboring organs (stomach,
duodenum).
- 10% show migratory thrombophlebitis (Trousseau
sign).
Adenocarcinoma Seen mostly in 7th decade; usually not diagnosed at Morphology: infiltrative / exophytic, found
of the resectable stage (most have invaded liver, cystic duct, mostly in fundus or neck.
Gallbladder or adjacent bile ducts) – poor prognosis.
~ gallstones present in 95% of cases; carcinogenic
derivatives of bile acids, irritation / inflammation from
stones may play a role in development.
Metastasis: regional nodes, peritoneum, lungs, GI
tract.
Bile Duct Multiple small (1-2mm) BENIGN white nodules in liver
Hamartoma near or within portal areas, made up of dilated
(Von Meyenburg irregular bile ducts.
Complex) - often clinically suggests metastatic carcinoma.
- circumscription & lack of atypia.

Focal Nodular Most common 20-50 yo; presents as liver mass, often
Hyperplasia with a central scar.
- all components of normal liver present; needle
biopsy nondiagnostic, pathogenesis uncertain.

Hepatic Most common benign tumor of liver; usually

Hemangioma cavernous type (large dilated vessels).
- possible clinical confusion with cancers.
Hepatic BENIGN hepatocyte tumor (NO portal tracts or central
Adenoma veins); most common in women using oral
contraceptives (may regress if drugs terminated).
- can rupture  serious (sometimes fatal)
hemorrhage.
- can be difficult to distinguish from well
differentiated hepatocellular carcinoma on needle
biopsy; rarely can transform into hepatocellular
carcinoma.
Hepatocellular 3rd most common cause of cancer deaths worldwide; Histo: atypical hepatocytes in trabecular
Carcinoma (HCC) 80+% occurs in developing countries w/ high rates of (similar to normal liver but with thicker
chronic hepatitis B; most in pts >50 yo, but can occur cords) or pseudoglandular pattern
in children. * most common diff. Dx of large round pink cell
Risk factors: cirrhosis, chronic viral hepatitis (esp. B & tumors = hepatocellular carcinoma, renal cell
C), alcoholism, non-alcoholic steatohepatitis, food carcinoma & adrenal cortical carcinoma.
contaminants (aflatoxin in peanuts, grains).
Gross: can be single mass, multiple nodules or diffuse
infiltration.
- bile production, if present, is strong evidence for
hepatocellular differentiation.
- often shows vascular invasion.
Clinical Features: usually correlated with cirrhosis 
ill-defined abdominal pain, malaise, fatigue,
abdominal fullness.
~ ↑serum -fetoprotein (AFP) in 50% cases; many
false (+)s; AFP elevation > 100x virtually diagnostic of
hepatocellular carcinoma or a germ cell tumor.
~ very poor prognosis ; screening w/ detection of
small tumors (< 2cm) can improve prognosis.
~ most deaths from liver failure, hemorrhage;
metastases can occur.
Fibrolamellar 5% of cases (mainly in young adults).
Variant of HCC ~ usually no underlying liver disease; cure rate ~ 50%
(much better than conventional HCC).
Morphology: large eosinophilic hepatocytes within
bands of collagen.
Hepatoblastoma Mainly in infants; composed of epithelial cells
resembling fetal hepatocytes, sometimes w/
immature small blue cells or mesenchymal
differentiation (bone, cartilage,muscle).
- poor prognosis w/o treatment, improved w/
chemotherapy & complete resection.
Cholangio- Adenocarcinoma arising from bile ducts; more
carcinoma common in southeast Asia due to biliary infection by
liver fluke (Opisthorchis sinensis).
~ most common site is extrahepatic ducts of liver
hilum (Klatskin tumor); intrahepatic tumors may show
mixed hepatocellular / cholangiocarcinoma
differentiation - may be difficult to exclude metastatic
carcinoma.
~ poor prognosis (median survival 6 months).
Hepatic Assoc. w/ exposure to vinyl chloride, arsenic or
Angiosarcoma thorotrast with latent period of decades.
~ poor prognosis (death in < 1 year).

Metastatic Tumors in the Liver are much more common than primary hepatic tumors – most common metastases are
from colon, breast, lung & pancreas; lesions are often multiple and disease is often extensive w/ absence of clinical and
laboratory evidence of liver insufficiency.

Emotional Factors in GI Disease – Eating Disorders.

70% of teenage women feel fat. 95% of women w/ anorexia start with normal dieting, 75 % of food restrictors exercise
to excess, 50-70% recover, 10-15% die. 95% of patients are women.

Anorexia Nervosa Bulimia Nervosa

- 15% below normal weight; preoccupation with weight
and thinness (distorted body image).
- amenorrhea ( 1/3 premorbid).
- restricting type, binge-Eating/purging type.
Clinical features: intense fear of gaining weight, resistant
to treatment, loss of appetite (anorexia) rare initially but
develops later; many are preoccupied with food and
cooking.
~ binging/purging subtypes lose control, binge then vomit
or use excessive exercise to lose weight.
~ obsessive compulsive behavior, depression, anxiety.
~ poor sexual adjustment in most, but some are
promiscuous.
~ 50% co-morbid major depressive disorder and suicide
risk (particularly in binging group).
Tx: If patient is 20% or more below normal weight, weight
restoration is the primary focus; psychotherapy and
antidepressants effective after weight is normalized.
- recurrent episodes of binge eating (feeling out of control
+ purging to prevent weight gain (self-induced vomiting,
misuse of laxatives, diuretics, enemas, or other
medications) / non-purging attempts to avoid weight gain
(fasting, excessive exercise).
- binge eating & compensatory behaviors occur on average
2 x / week for at least 3 months.
- disturbed body image; does not occur solely during
episodes of anorexia.
Causes: (1) biological - depression, low levels of serotonin
or NE; endorphins released during vomiting reinforce
behavior. (2) psychological - adolescence/impulsivity, lack
of superego control, difficulty in separating from maternal
figures, lack of ego strength. (3) social - pressure to be
thin.
Tx: cognitive therapy effective for 60-70% of patients;
antidepressants reduce binging and risk of relapse.

Eating Disorder NOS is characterized by (1) normal eating, but excessive exercise & purging, OR (2) binge eating w/o
purging, OR (3) weight loss and diet restriction w/o focus on weight or body image, OR (4) pica – eating non-nutritive
substances, i.e. dirt.
Risk Factors:
- family Hx of eating disorder, depression, alcohol abuse, obesity.
- premorbid experience: low self esteem, perfectionism, anxiety, OCD, obesity, early menarche, adverse parenting,
sexual abuse, family dieting, critical comments on eating / appearance / weight, occupational / recreational pressure to
be thin.
- personality risks:

Weight Control & Bariatric Surgery.

Gastric bypass surgery helps to lose excess weight and ↓ risk of potentially life-threatening health problems, including:
GERD, heart disease, hypertension, severe sleep apnea, DM II, stroke.
~ surgeries are typically done ONLY after failure of other means of losing weight.
Indications: (1) BMI is 40 or higher, (2) BMI is 35 – 39.9, and pt has serious weight-related health problem, (3) BMI is 30 –
34 and pt has multiple serious weight-related heath problems.
Before surgery: extensive screening process - patient must be willing to make permanent changes  healthier lifestyle.
Patient will agree to accept a long-term follow-up plan that includes monitoring nutrition, lifestyle, behavior, and
medical conditions; patient must be informed that surgery is expensive & not free from complications.
* Surgeries are elective - now performed laparoscopically.
Ideally, the patient should lose 33% to 50% of weight within 2 yrs after surgery!
Lap-Band Gastric Bypass

Reduces the size of stomach with or
without bypassing a length of GI tract.
Complications: thromboembolism,
dysphagia, band slippage. 1% mortality.
Best long term result, but technically
demanding; vitamin supplementation
required.
Complications: infection, pulmonary
embolism. 2% mortality.

1. To understand the rationale for this type of surgical intervention to treat obesity.
Bariatric surgery is used to help morbidly obese clients lose weight and keep it off - morbid obesity is defined as BMI of
40 or above, or at least twice the ideal weight  greatly ↑ risk of developing health conditions.
Candidates for surgery: morbidly obese, as well as severely obese individuals (BMI ≥ 35) + obesity-related health
problems. Surgery is considered if:
~ patient unable to reduce body weight by 1/3 or body fat by 1/2 over a reasonable time frame.
~ patient unable to maintain the weight loss achieved.
~ patient fails to lose weight via conventional method i.e. diet, exercise, behavior modification.
Aim: reduction of stomach size via restrictive procedures (Laparoscopic Gastric Banding, Sleeve Gastrectomy), rerouting
of digestive system, or a combination of both.
Gastric Banding is the most common type of bariatric surgery – carried out by reducing size of stomach & re-
routing digestive system to interfere w/ absorption of some calories.
2. To discuss the pre and post-operative dietary requirements associated with the surgical procedures.
Pre-op DIET Post-op DIET
Consists of clear liquid, bowel prep diet - prevents contamination AVOID nuts, seeds, popcorn, dried fruits,
from stool and allows the bowel to rest after surgery -- broths, granola, stringy or fibrous vegetables (broccoli,
herbal teas, sugar free popsicles. cabbage, corn, celery), candy bars, ice-cream,
Short-term prep: general reduction of total intake, attempt to lose tough meats & gristle.
10% of excess weight within a month prior to surgery should be Phase 1 – liquid diet (broth, unsweetened juice,
made; avoid dehydration! milk, strained cream soup, sugar-free gelatin, NO
 proteins – intake should be 1.0 – 1.5g / kg (1/4 – 1/2 cups); caffeinated or carbonated drinks).
weight loss surgical pts at risk of protein deficiency. Phase 2 – pureed foods 2-4 wks post-op (lean
*Supplements (soy, egg white milk-based products, protein isolates) ground meats, beans, fish, egg whites, yogurts,
are lactose free and well tolerated – available in clear liquids, shakes, soft drinks, vegetables, cottage cheese; fat free
powders & bars (to prevent loss of lean body mass). and sugar free recommended, avoid spicy
 fluids - ¼ cup sugar free, non-carbonated water every 15 mins foods).
(avoid water during meals to prevent Dumping Syndrome). Phase 3 – soft solid foods 4-8 wks post-op
 vitamins & minerals - start w/ chewable or liquid supplements (ground / finely diced meat, canned or soft
and progress to tablets as tolerated. vegetables, fruit and cooked vegetables).
~ give 100%-200% of daily value for 23 vitamins and minerals; Phase 4 – 8 wks & onwards: small amounts of
calcium citrate & Vitamin D to prevent bone disease; additional B12 regular food, allowing the body to heal; sip fluid
& iron in gastric bypass and vertical sleeve gastrectomies; B-complex about 64 ozs/day (straws cause distention!).
also recommended. *** Regular follow up important – monitor body
~ in highly malabsorptive surgeries (biliopancreatic fat loss, potential anemia, deficiencies of
diversion/duodenal switch), give fat soluble vitamins (A,D,E,K). potassium / magnesium, folate & B12.
3. To stress the appropriate dietary regime to reduce/prevent complications associated with the more austere types of
procedures. 4. To discuss appropriate vitamin and mineral supplementation. 5. To discuss the overall weight loss goals.
6. To be able to identify suitable candidates for such procedures. 7. To understand the guidelines and standards of
special care as outlined by the American Dietetic Association with respect to protein, fluids and fat intake. See above.
8. To discuss the signs, symptoms and prevention of dumping syndrome.
Symptoms of Intolerance: (1) vomiting is a cardinal symptom within 1st few months of surgery; Tx: ingestion of small
amounts of food slowly, thorough chewing. (2) Dumping Syndrome - osmotic overload in small intestines when high
sugar foods are consumed or when fluids are combined with a solid meal  nausea, diarrhea, tachycardia, sweating, gas
& abdominal cramps; Tx: small meals, slow eating (at least 30 min per meal), foods & liquids low in fat & sugar, wait at
least 30 min after meals to ingest fluids.

Pediatric GI Diseases.

Disease Presentation / Complications Dx / Management

Tracheo- Patients are often asymptomatic at birth;
esophageal may present w/ excessive drooling,
Fistula coughing, choking, regurgitation, or
cyanosis upon feeding.
~ aspiration can present as respiratory
distress, atelectasis, & pneumonia.
~ gastric distention & pulmonary
compression  compromised respiratory
status.
- Esophageal catheter & esophagogram - placement of catheter
into esophagus that does NOT pass into the stomach is usually
the first sign of esophageal atresia; standard barium swallow is
NOT recommended due to possible spillage into pulmonary tree.
Abdominal x-ray suggests
anomaly (gas in stomach & small
bowel  distal fistula; gassless
abdomen  esophageal atresia
w/o TEF or proximal fistula).
- Isolated TEF (usually presents in older child) can be
demonstrated with concurrent bronchoscopy & esophagoscopy.
- an echocardiogram should be performed (1) to rule out
presence of cardiac anomalies, (2) to determine the side of the
aortic arch - a left thoracotomy can be considered for a right-
sided aortic arch.
- an abdominal ultrasound is done to rule out renal anomalies
(part of VACTERL – vertebral, anal, cardiac, TEF, renal, & limb
syndrome).
- prenatal sonography can suggest esophageal atresia w/
findings of polyhydramnios & no visible stomach.
Tx: treat from birth w/ IV antibiotics & parenteral nutrition as
needed; reconstruction of air & food passage.
Pyloric Affects babies 2 – 8 weeks old, M > F Dx mainly by history & clinical examination; ultrasound is
Stenosis (presentation rare after 3 months); causes the best investigation:
non-bilious, forceful vomiting that can
lead to dehydration, starvation, weight
loss & fluid electrolyte abnormalities
(hypochloremic metabolic alkalosis).
~ most common problem requiring
surgery in newborns.
Signs: visible peristalsis aggravated by test Tx: IV fluid replacement, discontinuation of oral feeding,
feed, olive-shaped lump (~2 cm) palpated NG tube suction, pylorotomy under general anesthesia w/
in upper abdomen. endotracheal intubation & muscle relaxation.
Familial Most common genetic (autosomal Tx: FAP requires resection of the entire colon and rectum.
Adenomatous dominant or sporadic) polyposis
Polyposis syndrome  hundreds or thousands of
(FAP) polyps appear in colon & rectum.
~ may present with rectal bleeding or
anemia.
~ 80% develop adenoma by the age of 15;
rd th
most become malignant at about 3 or 4
decade of life.
~ upper GI tract may have polyps / malignancy
in 90% of cases (must be ruled out).
~ may be assoc. w/ extraintestinal features.
Peutz – Due to autosomal dominant abnormality on Chr. 19  tendency to form multiple hamartomatous
Jeghers polyps & cancerous tumors; most commonly seen in small bowel, malignant potential is low.
Syndrome ~ freckles on lips, mouth, around eyes, nose, anus, hands & feet - usually occur in infancy or childhood
and may fade with age.
Complications: bleeding, anemia, intussusception, malignancy.
* cancer may be assoc. w/other organs like pancreas, lung, breast & ovary.
GI Polyps Gardner's Syndrome involves presence of large #s of polyps in bowel; can cause other soft tissue
pathology (multiple epidermoid cyst, lipomata) and ↑ risk for bone & soft tissue cancers.
~risk of colorectal cancer is 100%!
Turcot's Syndrome involves a primary malignant brain tumor + multiple colon & rectal adenomas; may
have associated basal cell cancers of the scalp as well as stomach cancer.
Colon Cancers Commonly in distal colon; presents w/ Dx: colonoscopy and biopsy.
alteration of bowel habit, constipation, Imaging: plain and contrast x-rays, ultrasound, contrast CT
diarrhea, GI bleeding. and MRI, endoluminal USS and MRI.
~ Acute abdomen may occur due to Tx: radical surgery, radiotherapy, chemotherapy.
perforation, acute intestinal obstruction,
pericolic abscess, fistula formation.
Necrotizing Most common GI emergency in neonates Dx: x-ray shows fixed or distended loops, pneumatosis
Enterocolitis – typically seen in premature infants; intestinalis (presence of gas in intestinal wall), pneumo-
(NEC) formula feeds, impaired gut blood flow & peritoneum.
infection have been implicated.
~ intestinal infection develops, w/ potential
for extensive ulceration, necrosis, &
perforation  immature infants’ immune
system not adequate to cope.
~ ileum & colon most frequently affected.
Clinical features: poor feeding, bilious
vomiting, distended abdomen & blood in Tx: antibiotics, gut rest, parenteral nutrition & surgery.
stools. ~ 25% death rate, main prognostic factors are age of child
~ abdominal tenderness, periumbilical and initiation of treatment.
darkening or erythema; sepsis may be
 present.
* diarrhea in neonates after ingestion of
milk may be due to disaccharidase
deficiency.
Meckel’s ~ unobliterated part of vitello-intestinal Dx: imaging (usually not visualized by contrast radiography
Diverticulum duct; most prevalent congenital anomaly or CT scan); high enema is assoc. w/ 75% accuracy, but
of GIT - present in 2 % of cases, 2” in length, may produce complications in acute case; Technetium scan
2 ft proximal from ileocaecal junction, 1/2 may be useful if associated ectopic gastric mucosa is
present before 2 yrs of age, 1/2 cases have present (may take up the technetium).
heterotrophic epithelium, of which 1/2 is Tx: resection require if symptomatic.
gastric. * look for Meckel’s diverticulum is appendix is normal
~ usually asymptomatic, but may cause during acute appendicitis surgery.
hemorrhage (leading cause of rectal * if a silent Meckel’s diverticulum is found incidentally
bleeding in children), intussusception, during surgery, leave it alone unless the mouth is narrow
inflammation, chronic peptic ulceration or or the wall is thick.
intestinal obstruction. Prognosis of surgery is usually excellent.
~ NOT hereditary, malignancy very
unlikely.
Intus- ~ telescoping of one segment of intestine
susception into an adjacent distal segment - drags
associated mesentery, vessels, & nerves
with it, resulting in compression of veins,
followed by swelling  obstruction,
subsequent ↓ in blood flow to affected
part of the intestine.
^ color Doppler shows normal vascularization of the bowel walls in the
~ most cases affect ileocolic region.
intussusception.
***always consider intussusception in a
child who presents with colicky
Tx: resuscitation by IV fluid and nil by mouth, admin of IV
abdominal pain followed by vomiting.
antibiotics.
- most common cause of intestinal
~ intussusception can be reversed w/ barium enema (both
obstruction in children 3 mo – 6 yrs.
diagnostic & therapeutic!) under hydrostatic pressure.
Presentation: colicky abdominal pain,
~ surgery is indicated in: (1) failure of reduction by
bilious vomiting, and “red currant jelly"
hydrostatic pressure, (2) recurrent intussusception, (3)
stool (mixture of blood & mucus
intussusception secondary to malignancy, (4) unstable
squeezed out from apex of
patient.
intussusception; may be assoc. w/
gangrene).
 episodes of screaming & drawing up legs
of previously healthy child.
 sausage-shaped mass may be
palpated; concavity directed toward
umbilicus, emptiness of the right iliac
fossa.
Cystic Fibrosis See Dr. White’s lecture. Meconium ileus - thick viscid meconium (normally kept fluid by pancreatic
enzymes) may cause intestinal obstruction in terminal ileum.
Complications: intestinal perforation, volvulus. Other GI problems assoc. w/ CF include malabsorption,
steatorrhea, biliary cirrhosis & portal hypertension, gallstones.
Celiac T-cell mediated hypersensitivity reaction
Disease to wheat protein.
~ peaks in infancy and 50-60 yo.
~ presents w/ abdominal pain, bloating,
steatorrhea, weight loss, etc.
~ presence of serum anti-gliadin and anti-
endomysial antibodies.
Complications: anemia, lactose
intolerance, GI lymphomas & other
malignancies.
Gold standard investigation = endoscopic small bowel
biopsy (shows subtotal villous atrophy & migration of
activated lymphocytes from base to tip of intestinal villi).
Tx: Prolamin (gliadins & glutenins) produces the allergy -
lifelong avoidance is the best solution; repetition of
intestinal biopsy will show reversal to normal jejunum.
~ in rare cases, immunosuppressants may be used.

Burkitt’s Highly aggressive lymphoma Tx in both children & adults should begin within 48h of
Lymphoma characterized by diffuse infiltrate of diagnosis!
intermediate-size cells w/ high mitotic - use of intensive combination chemotherapy regimens
rate; spontaneous cell death (apoptosis) (high doses of Cyclophosphamide recommended).
 "starry sky" appearance caused by - prophylactic CNS therapy is mandatory.
numerous macrophages engulfing
apoptotic debris.
~ common in equatorial Africa; involves
children much more than adults, related
mostly EBV infection / AIDS.
~ characteristically high chance of
involving the jawbone, also commonly
involves the abdomen.

Urinalysis & Renal Function Tests.

1. Findings and interpretation of blood tests and urinalysis relevant to renal diseases.
Urinalysis: urine is easy to examine and gives significant
amount of information – (1) detection of disease processes
extrinsic & intrinsic to the urinary system, functional &
structural, (2) progression & regression of various lesions can
be monitored, (3) systemic disease processes such as endocrine
disorders or metabolic abnormalities can be detected.
- urinalysis includes physical, chemical (dipstick), microscopic &
microbiologic exam.

Examples:
CASTS (see above): formed only in the DCT or collecting duct; hyaline casts are non-specific (can occur in low urine flow,
concentrated urine, acidic environment as in dehydration or vigorous exercise) while RBC casts signify
glomerulonephritis. Urinary casts are cemented together by Tamm-Horsfall mucoprotein.
~ Factors that favor protein cast formation include slow flow rate, high salt concentration, and low pH – these cause
denaturation & precipitation of proteins, esp. Tamm-Horsfall.

KEY POINTS:
~ dysmorphic RBCs are often a sign of glomerular disease; RBCs from any point along the urinary tract can form casts in
the renal DCT.
~ specific gravity & osmolality measurements reflect the concentrating ability of the kidney.
~ proteinuria should be further investigated - 3.5 gms/day is seen in nephrotic syndrome; ketonuria is seen in diabetes,
cachexia and febrile illness.
~ dipstick nitrite and leukocyte esterase are used to diagnose urinary tract infections - positive results should be verified
by microscopy & culture.
~ urinary calculi are most commonly formed w/ calcium - work-up should include analysis of both the urine and stone.
2. Azotemia vs. uremia.
Azotemia Uremia
↑ blood urea nitrogen (BUN) and Azotemia + other biochemical abnormalities + clinical findings of renal
creatinine levels due to ↓ glomerular disease.
filtration rate (GFR). Metabolic abnormalities:
Causes: (1) pre-renal – reduced blood flow ~ acidosis: ↓ acid excretion and ↓ bicarbonate reabsorption.
to kidneys, (2) renal – kidney disease, (3) ~ retention of water, PO4, Na+, K+; low serum Ca++.
post-renal – obstruction of urine flow. ~ loss of kidney parenchyma  ↓ hydroxycalciferol activation  ↓
* If BUN:Cr ratio > 20:1, it is pre-renal ARF intestinal absorption of Ca ++  calciuria.
(creatinine essentially not reabsorbed). Systemic manifestations: dehydration, edema, hyperkalemia, metabolic
* If BUN:Cr ratio is 10:1, it is a normal acidosis, hyperphosphatemia, hypocalcemia, secondary
kidney or renal disease (i.e. both BUN and hyperparathyroidism, renal osteodystrophy, anemia, bleeding diathesis,
creatinine not excreted, so ratio remains hypertension, CHF, pulmonary edema, uremic pericarditis, nausea,
the same). vomiting, GI bleeds, esophagitis, gastritis, colitis, pruritis, dermatitis,
myopathy, peripheral neuropathy, encephalopathy.
3. Acute vs. chronic renal failure.
ACUTE RENAL FAILURE CHRONIC RENAL FAILURE
Markedly ↓ urine flow (oliguria) or no renal flow (anuria); Characterized by prolonged uremia (months – years).
recent onset azotemia. ~ chronic, progressive & irreversible deterioration (> 3
mo), leading to end-stage renal disease (GFR < 20 mL).
Causes: (1) diabetes mellitus - glycemic control is critical to
slow progression, (2) hypertension, (3) glomerulonephritis,
(4) polycystic kidney disease, (5) urologic disease – chronic
UTIs, nephrolithiasis, (6) vasculitis, i.e. SLE, (7) drug
toxicity, (8) unknown.
Dx: azotemia  uremia (Cr > 4 mg/dL), reduced GFR (< 60
mL / min); serum shows metabolic acidosis, ↓ serum Ca++,
retention of Na+, K+, and phosphate; urinalysis shows
waxy & broad casts.
Complications: (1) hypertension and congestive heart
failure due to water and solute retention, (2) renal
osteodystrophy (osteomalacia + osteitis fibrosa cystica)
due to phosphate retention & low Ca++, (3) normocytic
anemia (↓ erythropoietin production in kidney), (3)
* Pre-renal causes of ARF are commonly seen in hemorrhagic diathesis due to altered platelet function, (4)
hospitalized pts – burns, loss of blood volume, prolonged uremia.
vomiting / diarrhea / bleeding, heart failure, shock,
surgery, trauma, renal artery embolism / occlusion.
4. Define the major clinical manifestations of renal disease and develop a differential diagnosis for their etiology:
nephritic syndrome, rapidly progressive glomerulonephritis, nephrotic syndrome, isolated urinary abnormalities, renal
infections, renal lithiasis.
I. Nephritic Syndrome – hematuria (blood in urine) due to glomerular disease – red casts & dysmorphic RBCs on
urinalysis. Usually characterized by azotemia, oliguria (due to ↓ GFR), & hypertension; mild proteinuria (1-3 g/day) &
edema also common.
~ most commonly caused by post-streptococcal glomerulonephritis.
II. Rapidly Progressive Glomerulonephritis – nephritic syndrome + rapid decline in GFR (essentially nephritic syndrome +
acute renal failure); renal function declines in a matter of days – weeks.
 mild to moderate proteinuria, microscopic glomerular hematuria, RBC casts, oliguria / anuria (urinary output
<0.3ml/kg/h for 24h or anuria for 12 hours).
~ causes include (1) anti-GBM – idiopathic, Goodpasture Syndrome, (2) immune complex – idiopathic, infection-related,
SLE, Henoch-Schonlein purpura / IgA nephropathy, (3) ANCA-associated – idiopathic, Wegener’s granulomatosis,
microscopic angiitis.
III. Nephrotic Syndrome – characterized by heavy proteinuria (> 3.5 g/day), hypoabuminemia, severe edema (due to ↓
albumin), hyperlipidemia, lipiduria (lipid in urine/fatty casts).

Other proteins lost in urine include (1) Igs & complement  impaired
immune response, (2) clotting & anti-clotting proteins  thrombosis, (3)
proteins that carry other blood components  imbalances, altered drug
dosages.

Elevated plasma lipids ↑ risk of atherosclerosis & progression of

glomerular injury.

~ major causes of nephrotic syndrome include (1) primary

glomerulonephritides – minimal change disease, focal segmental
glomerulosclerosis, membranous GN, membrano-proliferative GN, (2)
systemic diseases – diabetes mellitus, amyloidosis, SLE (lupus nephritis –
Class V).

SEE LAST LECTURE (below).

IV. Non-Glomerular Hematuria – urine is red (not brown), urinalysis shows no RBC casts.
~ causes include (1) polycystic kidneys  hypertension & flank pain, (2) urolithiasis or renal infarction  flank pain and
renal colic, (3) renal and bladder cancer  mass, (4) acute cystitis  urinary frequency and dysuria.
V. Urinary Tract Infection – characterized by bacteriuria (> 105-6 colonies/mL cultured urine), pyuria (WBCs in urine),
WBC casts; symptoms include flank pain, fever, chills.
~ types: pyelonephritis, cystitis, urethritis.
VI. Urolithiasis – urinary stones passing through ureter cause renal colic (severe pain in flank / lower back, radiating to
groin / genitals); urinalysis shows hematuria (non-glomerular – “fresh” RBCs, no casts, no dysmorphic RBCs).
~ causes include (1) ↓ water intake and/or ↑ concentration of urinary solutes, (2) alterations in urine pH, (3) Proteus
infection (“staghorn stone”).

Urinary Tract Infections.

1. Define urinary tract infection (UTI). UTI refers to infection of the bladder or kidney; characterized by bacteriuria.
Risk factors: F (20-40 yo) > M, sexual intercourse (↑ E. coli), contraceptives (spermicide, diaphragms), pregnancy
(untreated asymptomatic infections can lead to perinatal death!), indwelling urinary catheters, any condition that
interferes w/ emptying of urinary tract (neurological problem, prostate enlargement / BPH, ureteric reflux, renal stones,
etc), diabetes mellitus (neuropathy + impaired immune system + hyperglycemia).
- anticholinergics ↓ bladder tone, resulting in incomplete emptying and risk of UTI.
- postmenopausal women have less estrogen, leading to changes in vaginal flora & risk of UTI.
2. Understand the classification of urinary tract infections based on anatomic site in terms of the following: predisposing
risk factors, signs and symptoms (clinical features), physical examination findings, laboratory diagnosis, treatment,
prevention strategies.
Traditional classification of symptomatic bacteriuria based on anatomical site of origin:
Lower UTI – cystitis, urethritis, prostatitis.
Upper UTI – pyelonephritis, intrarenal abscess, perinephric abscess, emphysematous pyelonephritis.
 3. Describe the correct method for the collection of a midstream
clean-catch urine.
Types of urine specimens: (1) mid-stream clean catch, (2) random
urine, (3) supra-pubic aspiration – sterile.
* do NOT use catheter!
4. Name and describe the 3 components of a complete urinalysis. A
complete urinalysis consists of (1) macroscopic exam – color & clarity,
(2) chemical (dipstick) analysis – see below, (3) microscopic exam of
sediment – centrifuge, decant supernatant, resuspend sediment, &
view under microscope.
* CENTRIFUGED urine sediment may reveal RBCs, WBCs, mucus,
various epithelial cells, crystals, & casts, bacteria, yeast.

5. Explain the use and significance of the dipstick tests for leukocyte esterase and nitrite to rapidly screen a urine
specimen for an infection. Rapid urine dipstick screening tests include:

Leukocyte Esterase Test Nitrate  Nitrite Test

Principle: detects esterase enzyme present in whole or Principle: certain bacteria convert nitrate to nitrite (E. coli
lysed WBCs. and all members of Enterobacteriaceae).
Normal = negative or trace amount. Normal = negative.
If LE test is (+), it signifies pyuria (presence of WBCs) - If nitrate is reduced to nitrite, Nitrite test is (+).
indicator of urinary tract infection if pt has symptoms + If Nitrite test is (-) and LE test is (+), other bacteria (e.g.,
significant bacteriuria. Enterococcus spp. and Staphylococcus saprophyticus) may
~ vaginal discharge  false (+). be responsible.
If LE test is (-), no need to perform microscopic exam
and/or urine C&S – patient does not have infection.
6. Explain why an uncentrifuged urine is used to perform a Gram stain and a quantitative urine culture. 7. Describe the
purpose and method used to perform a quantitative urine culture. 8. Interpret the results of a quantitative urine culture.
A small volume of uncentrifuged urine is plated on sheep blood agar (non-selective) and MacConkey agar (selective for
Gram neg rods) – blood agar is used for colony count (CFU).

9. Interpret a Gram stain of uncentrifuged urine and explain how it relates to a quantitative urine culture.
The “quick & dirty” method of quantifying bacteria involves Gram stain of
uncentrifuged urine: ≥ 1 organism per oil immersion field = ≥ 105 or ≥
100,000 CFU/mL.

10. Define “significant bacteriuria” as it relates to a quantitative urine culture and whether the patient is symptomatic or
asymptomatic. See above.
Asymptomatic bacteriuria (≥ 10 CFU/mL urine in male or female without symptoms of a UTI) is more common in
pregnancy, diabetic pts, & men > 65 yo.
- in adult, non-pregnant patients w/o urinary tract obstruction (i.e. BPH), antibiotics are NOT given.
- in pregnant women, screening & antibiotic Tx is needed to ↓ incidence of pyelonephritis later in pregnancy, low birth
weight, and prematurity.
11. Name the most common causative organism in community-acquired and nosocomially-acquired urinary tract
infections.
I. E. coli - leading cause of nosocomial and community-acquired
UTIs; Nitrite (+); normal GIT flora - colon  vagina & urethra 
ascending UTI.
~ Type 1 pili or P fimbriae are major virulence factors that help E. coli
adherence to mucosa (uropathogenic).
II. Proteus – Gram (-) bacillus w/ “swarming motility” found in human
colon or water; Nitrite (+), urease (+); more commonly causes UTIs in
hospitalized or catheterized pts, institutionalized elderly.
~ urease ↑ pH and may cause ammonia odor, kidney stones
(Staghorn) esp. in recurrent infections.
III. Klebsiella pneumoniae - Gram (-) bacillus,Nitrite (+); found in
feces, water (normal GI flora); similar to E. coli infection, but not as
common.

IV. Staphylococcus saprophyticus – Gram (+) cocci in clusters, catalase (+) & coagulase (-); Nitrite (-); resistant to
novobiocin. Generally causes ONLY lower UTIs.
~ common in young, sexually active females (2nd to E. coli) - “honeymoon cystitis”.
~ ↑ incidence in postmenopausal women
V. Enterococcus faecalis – Gram (+) cocci in chains, Group D strep, catalase (-), Nitrite (-); more resistant to antibiotics.
~ common in pts w/ BPH.

Viruses (Adenovirus, BK virus) can also cause UTIs – primarily in immunocompromised pts & BM transplant recipients 
acute hemorrhagic cystitis (painful hematuria & passage of blood clots in urine).

Polyuria.

1. Define polyuria. Polyuria is defined as urine output of more than 2.5 – 3.0 L/day.
Mechanisms of polyuria: (1) ↑ intake of fluids – psychogenic, related to stress or anxiety, (2) ↑ GFR – seen in
hyperthyroidism, fever, hypermetabolism, (3) ↑ output of solutes – seen in diabetes mellitus, hyperthyroidism,
hyperparathyroidism, diuretic use, (4) inability of kidney to reabsorb water in DCT due to diabetes insipidus, drugs,
chronic renal failure.
2. Explain the important causes of polyuria.
3. Explain the difference between water and solute diuresis.
Water diuresis (urine osmolarity < 250 mOsm/kg; urine specific gravity < 1.010; solute concentration rate < 1) may be
caused by central or nephrogenic diabetes insipidus (deficiency of ADH or renal resistance to ADH). Solute diuresis
(urine osmolarity > 300 mOsm/kg; urine specific gravity ≥ 1.010; solute concentration rate > 1) may be caused by
hyperglycemia, excess protein intake by gastric tube, or salt-losing nephropathy.
4. Describe the symptoms and signs of some important disorders causing polyuria.
CENTRAL DIABETES INSIPIDUS. Signs & Symptoms: polyuria & polydipsia, abrupt onset, normal/high-normal serum Na+.
Causes: (1) idiopathic (75%) - may be familial; characterized by nerve degeneration in hypothalamic nucleus, (2)
neurosurgical – craniopharyngioma, trans-sphenoidal surgery, (3) head trauma, (4) ischemic encephalopathy or hypoxia,
(5) neoplasm, (6) miscellaneous causes, i.e. pregnancy.
NEPHROGENIC DIABETES INSIPIDUS. Signs & Symptoms: polyuria & polydypsia, gradual onset.
Causes: (1) acquired (more common) – chronic renal disease, electrolyte disorders, drugs (i.e. Lithium), (2) congenital /
hereditary – polycystic kidney, medullary cystic disease.
PRIMARY POLYDIPSIA. Signs: hypotonia, polyuria, polydipsia. Lab: serum Na+ usually normal or slightly ↓ (rare cases of
lethal hyponatremia); urine osmolality 600-800 after water deprivation test, < 10% increase in osmolality after inhalation
of dDAVP (desmopressin).
Causes: (1) psychological disorders – delusions, depression, agitation, hysterical behavior; water consumption is irregular
from hr to hr and day to day, (2) hypothalamic disorders , e.g. sarcoidosis.
SIADH. (syndrome of inappropriate ADH secretion) often accompanied by long-term heavy smoking  evidence of
mass in lung, malignant cells in sputum (small cell carcinoma of the lung).
~ characterized by hyponatremia w/ low plasma osmolality + highly concentrated and ↓ volume of urine.
5. Diagnose a patient with polyuria, work through some cases of polyuria.

Water Deprivation Test requires no coffee, tea, smoking or

oral intake (from 7:30am) on test day; body weight, plasma
and urine osmolality are recorded at the start of the test
and every hr during the test – STOP test is patient loses 3%
body weight!
~ plasma and urine tests repeated after dDAVP
(desmopressin) given by nasal spray.

 results.

Developmental Genetic Disorders.

Condition Pathology Morphology

Renal Kidney(s) not formed - bilateral agenesis is fatal & often
Agenesis assoc. w/ other abnormalities (usually in stillborn
infants), unilateral agenesis may be compatible w/
normal life (2nd kidney undergoes compensatory
hypertrophy).
Renal Usually unilateral; may result in childhood renal failure if Kidney is small w/ reduced lobes & pyramids
Hypoplasia bilateral. Differentiate from acquired scarring / atrophy! (6 or less – normally 8 or more).
Ectopic Kidney in wrong place - USUALLY IN OR JUST ABOVE THE
Kidney PELVIS; may have kinked or tortuous ureter  partial
obstruction, urinary stasis & bacterial infection.

Horseshoe Common (1 / 500-1000 autopsies); fused in lower pole in

Kidney most cases – usually does not cause problems.
Renal Sporadic abnormality in differentiation - usually enlarged Cartilage, loose
Dysplasia & cystic (most common cystic disease in children & most undifferentiated
common cause of abdominal mass in newborns). mesenchyme,
~ commonly assoc. w/ other anomalies of lower urinary immature
tract (i.e. ureteropelvic obstruction). glomeruli &
~ unilateral  good prognosis, bilateral  risk of renal tubules.
failure.
Autosomal Most common polycystic disease, characterized by
Dominant expanding cysts that destroy renal parenchyma and
Polycystic cause renal failure. Pathogenesis: mutation in PKD1 (more
Kidney common) or PKD2 genes that encode Polycystin-1 and
Disease Polycystin-2 proteins - causes 5 -10% of chronic renal failure;
(ADPKD) risk of renal failure ↑ w/ age (usually by age 60).
* ALWAYS BILATERAL (if unilateral, consider cystic
neoplasm, such as renal cell carcinoma). Kidneys are
enlarged (up to 4 kg), parenchyma replaced by 3 – 4cm
cysts  may present w/ asymptomatic renal
insufficiency, hematuria, pain or mass.
Associated pathology: hepatic cysts (40%), splenic cysts,
berry aneurysms in Circle of Willis (may cause
intracranial hemorrhage), mitral valve prolapse.
Autosomal Rare disease w/ cystic dilatation of collecting ducts,
Recessive caused by mutation in PKHD1 gene that encodes
Polycystic Fibrocystin protein – usually presents at birth w/ renal
Kidney failure
Disease * ALWAYS BILATERAL; multiple small cysts (<1 cm) within
(ARPKD) cortex & medulla  “spongiform kidneys”.
* Liver involvement: multiple cysts and proliferation of
bile ductules w/ fibrosis (congenital hepatic fibrosis).
Acquired (1) Dialysis-associated cystic disease – seen in 75% pts >
Cysts 5 yrs on dialysis; cysts are multiple and found in both
renal cortex & medulla.
~ may progress to renal cell carcinoma.
(2) Simple cysts – common incidental finding on autopsy;
cysts are single or multiple, 1-10cm in diameter, and
usually found in subcapsular renal cortex.
~ rarely produces symptoms, but may simulate a tumor
clinically.
Alport’s Presents in childhood w/ hematuria (may later have Glomerular basement membranes show
Syndrome proteinuria & nephrotic syndrome); renal failure in irregular thinning & thickening + split /
adults. laminated lamina densa on EM (caused by
 nerve deafness (may be subtle) and eye disorders. injury & remodeling).
* 85% X-linked inheritance (males have full syndrome, females
usually only hematuria). Autosomal recessive & dominant
forms also exist (females fully affected).
Pathogenesis: defective assembly of type IV collagen in
GBM - immunostaining for certain subunits (alpha 3,4
and 5) of type IV collagen are negative (helpful in Dx).
LM shows non-specific glomerular changes,
interstitial fibrosis w/ foam cells, mesangial
hypercellularity & sclerosis (focal segmental
or general); absence of Ig deposition.
Thin Asymptomatic hematuria (sometimes + proteinuria) due GBM is thin (150-250nm); normal =300-400.
Basement to mutations in genes encoding alpha chains of type IV
Membrane collagen (most are heterozygotes w/ normal kidney
Lesion function & excellent prognosis; rare homozygotes may
(Benign progress to renal failure, i.e. Alport Syndrome).
Familial
Hematuria)

Kidney graft rejection can be:
HYPERACUTE
Occurs min-hrs after transplant
(surgeon often notes cyanotic changes
while still in operating room).
- results from pre-formed antibodies
against donor (previous pregnancy,
blood transfusion, or transplant).
- Abs react against donor vessels
causing widespread thrombosis 
necrosis & graft failure.
ACUTE
Occurs days-yrs after transplant.
(1) Cellular rejection: lymphocytes
invade interstitium, tubules (tubulitis)
or endothelium (endothelitis).
(2) Humoral rejection: antibodies
bind to blood vessels  deposition of
complement breakdown product C4d.
- lymphocytic infiltrate, vasculitis.
Renal Transplant Pathology.
Rejection occurs when recipient’s
immune system recognizes organ as
foreign – cell-mediated immunity +
circulating Abs involved. Measures
to prevent rejection include pre-op
antigen matching & post-op
immunosuppressive drugs.
- Donors are selected based on good
renal function, no infection, no
malignancy or systemic disease,
short warm ischemic time,
psychological soundness, and
excellent health.
- Recipients are selected based on
ABO compatibility, (-) serum cross-
match w/ donor, & closest possible
HLA match (esp. at D loci).
* Unless diseased kidneys are
causing problems, they should be
left in place during transplant
CHRONIC
Occurs mths-yrs after transplant.
~ slow progressive renal failure.
~ characterized by interstitial fibrosis,
tubular atrophy, obliterative intimal
fibrosis, glomerular fibrosis,
thickening of GBM (transplant
glomerulopathy).
Edema.

1. Define edema. 2. Explain physiology of body fluids. 3. Explain the differences between transudate and exudate.

Edema is the clinically apparent ↑ in interstitial

fluid volume (the extra-vascular portion of
extracellular compartment); edema is not
necessarily accompanied by cellular swelling
and plasma volume may or may not be
increased.
~ volume may expand by several liters before
abnormality is evident.

4. Explain the pathophysiology of edema.

I. Increased capillary hydrostatic pressure is caused by ↑ plasma volume, ↑ venous pressure (general as in congestive
heart failure or localized as in venous thrombosis), arteriolar dilation (i.e. acute inflammation).
Increased capillary hydrostatic pressure  increased force driving fluid into interstitium  increased formation of interstitial fluid
until > lymphatic compensatory return  edema.
~ Congestive heart failure involves ↑ central venous pressure and ↓ renal perfusion (which leads to ↑ renin, renal
vasoconstriction, & ↑ ADH).

~ Venous thrombosis – DVT can occur due to long periods of immobilization + other risk factors; Dx by D-dimer testing,
helical CT scan, & doppler ultrasound scan of suspected lower extremity.
- Homan’s Sign (+ when there is resistance in calf or popliteal region when pt’s foot is abruptly dorsiflexed at
ankle while knee is fully extended) also suggests DVT.
II. Reduced plasma oncotic pressure can result from ↑ protein loss or ↓ protein synthesis (albumin most important).
Causes: (1) ↑ albumin loss due to nephrotic syndrome – increased permeability of glomerular basement membrane, (2)
reduced albumin synthesis due to hepatic cirrhosis or protein malnutrition, (3) protein losing enteropathy or elevated
catabolism of proteins, i.e. malignancy.
III. Inflammation (both acute and chronic) causes increased capillary permeability  edema.
IV. Lymphatic obstruction - during interstitial fluid formation, 1/10 fluid that leaves the capillary at arterial end returns
to venous circulation via lymphatics - obstruction of lymphatics results in edema (usually localized due to inflammation
or neoplasia).
Neoplasia: Resection and/or radiation of axillary
Filariasis: parasitic infection affecting inguinal lymphatics lymphatics can lead to arm edema. Carcinoma of
& sometimes resulting in elephantiasis; caused by filarial breast w/ obstruction of superficial lymphatics can lead
worms transmitted into blood by mosquitos. to “peau d’ orange“appearance of breast.

V. Idiopathic edema is mostly observed in women & characterized by diurnal alterations in weight + orthostatic (upright)
retention of sodium and water. ( orange peel)
~ ↑ capillary permeability – fluctuates in severity, aggravated by hot weather.
~ ↓ plasma volume, secondary to activation of the RAA system
~ can be paradoxically induced or aggravated by diuretics!
~ Tx: reassurance, support, elevation of feet, Spironolactone, ACEI, ARB, etc.
VI. Iatrogenic edema may be induced by NSAIDs, vasodilators – Ca++ channel blockers, steroids – estrogens, IL-2,
Cyclosporine.
5. Describe some prototypical causes of edema. See above. 6. Describe the grading & morphology of edema.
Edema is documented according to type
(pitting, nonpitting or brawny); to grade
edema, palpate area and firmly apply
pressure with thumb for 5 sec - the
degree of edema is based on the depth
of indentation in millimeters.

Tubulointerstitial Disease.

Tubular & interstitial diseases include acute kidney injury (ischemic, toxic, etc) and tubulointerstitial nephritis
(infections, drugs & toxins, etc).

Condition Causes Pathogenesis Clinical

Acute Kidney (1) ischemia – i.e. Phases: (1) initiation
Injury (Acute massive hemorrhage, (36 hr) dominated
Tubular septic shock, severe by precipitating
Necrosis) is the burns, dehydration, event, e.g. trauma,
most common prolonged diarrhea, (2) maintenance
cause of acute congestive heart failure, (several days) 
renal failure, volume redistribution in oliguria, salt & water
usually due to pancreatitis / peritonitis. overload,
tubular damage
(2) nephrotoxins – hyperkalemia,
from ischemia or
toxins (tubules
antibiotics, radiographic uremia, (3) recovery
sensitive to contrast agents, heavy (days – months) 
injury due to metals, organic solvents polyuria,
high metabolic (e.g. ethylene glycol), hypokalemia,
Ischemic ATN Toxic ATN
rate). poisons (e.g. paraquat). improved BUN & Cr.
- segmental injury of - extensive cell injury &
(3) heme proteins – * up to 50% do NOT go
tubular epithelium; patchy necrosis of PCT & loop of
myoglobin, hemoglobin. through oliguric stage;
necrosis in proximal Henle epithelium.
may only have ↑ urine
tubule & loop of Henle, - eosinophilic & dirty
vol. Prognosis is good
necrotic debris in tubular granular casts seen in
lumen. distal tubules & if systemic damage
- tubulorrhexis: BM collecting ducts; from precipitating
rupture; inflammatory glomeruli NOT affected. cause is not extensive;
infiltration of interstitium. RED, SWOLLEN CORTEX. manage water balance
PALE, SWOLLEN CORTEX. & electrolytes; may
require temporary
dialysis.
Obstructive
Uropathy (UT
obstruction)
causes ↑ risk
of infection &
stone
formation and
can result in
permanent
renal atrophy
(hydronephrosis)
– dilatation of
renal pelvis &
- obstruction due to
calyces +
atrophy. calculi, tumors, clots,
inflammation, pregnancy,
etc.
Acute ~ Acute pyelonephritis
Pyelonephritis usually due to bacterial
infection.
Routes of infection:
(1) ascending - usually
from colonization of
distal urethra by
intestinal bacteria
(common agents = E. coli,
Proteus, Enterobacter,
Klebsiella, Serratia);
infection ascends to
bladder, ureters &
kidney.
* risk factors: females
(shorter urethra), urine
stasis in bladder
(obstruction),instrumenta
tion (catheter),
vesicoureteral reflux
(children), intrarenal
reflux (flat renal papillae).
(2) descending
(hematogenous infection)
is caused by Gram (+)
pyogenic bacteria (i.e.
infective endocarditis),
fungi & viruses (IC pts).
Chronic ~ Chronic pyelonephritis
pyelonephritis usually due to bacterial
infection (UTI) assoc. w/
vesico-ureteral reflux or
obstruction.
Obstruction (unilateral or bilateral, usually partial) causes dilation of
pelvis & calyces due to back pressure.
~ initially, trapped filtrate is reabsorbed by lymphatics & vascular route,
but continued obstruction ultimately reduces glomerular blood flow &
GFR.
~ prolonged back pressure  hydronephrosis.
Histo: backed-up fluid seen in
Bowman’s capsule;
glomeruli replaced by global
sclerosis; interstitial fibrosis &
inflammation; tubules distended
by proteinaceous material.
Gross: enlarged / swollen kidneys with small Signs & Symps: flank
abscesses (bilateral or unilateral). pain, spiking fever,
Histo: acute inflammation – neutrophilic chills, malaise,
infiltration of tubules & interstitium. nausea & vomiting,
dysuria, urinary
frequency &
urgency, costo-
vertebral angle
tenderness.
Urinalysis: pyuria,
WBC casts, epithelial
casts, bacteriuria,
Complications: (1) papillary necrosis – coagulative hematuria.
necrosis of renal papillae seen in obstruction,
diabetes, analgesic nephropathy, (2) pyonephrosis
– accumulation of pus in renal pelvis & calyces, (3)
perinephric abscess – abscess breaches renal
capsule, (4) pyelonephritic scar (after healing).
Gross: irregular scarring, broad depressed areas of Reflux nephropathy
cortical fibrosis overlying dilated, blunted or (chronic) presents as
deformed calyx; papilla flattened. recurrent UTIs,
Histo: interstitial fibrosis & mononuclear infiltrate; diagnosed by voiding
cystogram (shows
“thyroidization” - dilated tubules w/ hyaline casts.
 * Xanthogranulomatous ~ glomeruli spared initially, but may become retrograde flux of
pyelonephritis is an sclerotic. urine from bladder to
unusual form assoc. w/ ureter).
obstruction + Proteus Signs & Symps:
infection - can simulate gradual insidious
renal cell carcinoma onset (or may begin
grossly (yellow nodules) as acute PN), renal
and histologically (many insufficiency / HTN,
clear cells due to foamy slowly progressive
macrophages, aka renal failure.
xanthoma cells). Urinalysis: pyuria
(WBCs), polyuria &
 Xanthogranulomatous pyelonephritis: nocturia ( tubular
function); epithelial,
granular, & some
WBC casts +/-
bacteriuria.
Radiology:
asymmetrically
scarred kidneys,
blunting & deformity
of calyces.
Acute Drug- Hypersensitivity reaction Interstitial inflammation by mononuclear cells Fever, eosinophilia
Induced that begins about 15 days (lymphocytes & macrophages), eosinophils & (may be transient),
Interstitial after exposure to a drug. neutrophils may be prominent; granulomas may rash (25%), &renal
Nephritis ~ most common w/ be present. abnormalities
antibiotics, diuretics, & ~ infiltrate commonly extendx into tubules. (azotemia to acute
NSAIDs. renal failure).
Tx: withdraw drug!
Urinalysis:
eosinophils /
eosinophil casts.

Analgesic Chronic renal disease  Tubulointerstitial nephritis & papillary necrosis

Nephropathy from excessive intake of + calcification
analgesics - usually from . ~ papillary necrosis occurs first, impeded urine
mixtures w/ Phenacetin. outflow causes interstitial nephritis.
~ can be induced ~ may cause renal failure.
experimentally w/ high
dose Phenacetin +
Aspirin + water
depletion.
Urate Includes acute uric acid I. Acute uric acid nephropathy: precipitation of uric
Nephropathy nephropathy, chronic uric acid crystals in tubules/collecting ducts 
acid nephropathy, & obstruction of nephrons  acute renal failure.
nephrolithiasis (uric acid ~ most common in pts on chemo for
stones). lymphoma/leukemia (↑cell breakdown).
~ precipitation of urate ↑ by acidic PH in
collecting ducts.
II. Chronic uric acid nephropathy: uric acid crystals
in tubules/collecting ducts/interstitium due to
chronic hyperuricemia (gout) - obstruction 
cortical atrophy & scarring.
 ~ often seen in pts w/ gout + lead exposure (such
as “moonshine” whiskey).
Myeloma ~ light chain nephropathy - light chains combine w/ urinary
Kidney (renal
glycoprotein  casts obstruct tubules.
diseases assoc.
~ amyloidosis.
w/ multiple
~ light chain deposition disease - light chains deposited in
myeloma)
glomeruli  glomerulopathy, tubulinterstitial nephritis.
~ hypercalcemia/hyperuricemia  stones.

Glomerulonephritis I.

1. Functional anatomy, histology and ultrastructure of the kidney.

Kidneys have an end-artery system (no collateral circulation), so compromised blood supply leads to damage. Filtration
occurs in the glomerulus – the glomerular barrier is a complex structure, with different channels and charges (this is
why, for instance blood can get through in nephritic syndrome and protein in nephrotic syndrome, but not vice versa).

2. Diagnosis of glomerular pathology. Diagnosis of glomerular pathology involves renal needle biopsy, H&E stain +/-
special stains (silver, PAS, trichrome), immunofluorescence microscopy, & electron microscopy (EM).
~ pathology can be described according to glomerular involvement:
- diffuse (> 50% of all glomeruli) vs. focal (< 50% of all glomeruli).
- global (entire glomerulus) vs. segmental (part of glomerulus) vs. mesangial (mesangium).
The majority of glomerulonephritides are diffuse & global; crescentic GN can be diffuse or focal, lupus nephritis can be
diffuse or focal; focal segmental glomerulosclerosis is a type of primary GN.

Histological changes: (1) Hypercellularity - leukocyte infiltration

(neutrophils, monocytes, & lymphocytes), cellular proliferation
(mesangial, endothelial cells, parietal epithelial cells of Bowman
Capsule  crescent formation, (2) GBM changes (“wire loop”
subendothelial deposits suggestive of lupus), (3) Hyalinization
and sclerosis.

* Immune complex deposits can be found in the mesangium, in the subepithelial / epimembranous space (between
epithelial cells and GBM), in the subendothelium (between endothelial cells and GBM). For example, post-streptococcal
glomerulonephritis is characterized by “humps” – deposits under epithelium, on top of GBM. In Type II membrano-
proliferative GN, the entire GBM is transformed into a large immune deposit.
3. Mechanism, mediators and progression of glomerular injury.
Immune Mechanisms of Glomerular Injury:
Ab-mediated injury – in situ immune complex deposition (i.e. anti-GBM disease – antibodies to glomerular basement
membrane attach in the glomerulus, causing immune response), circulating immune complexes (i.e. lupus – circulating
complexes become trapped in the glomerulus).
 Peripheral granular pattern on
immunofluorescence - immune deposits on
GBM, seen in membranous GN; Peripheral
linear pattern seen in anti-GBM disease
(sometimes diabetes as well).

4. Introduction to disorders of glomerular function.

Different presentations can point to different forms of glomerular disease.
Disease Pathology Presentation
NEPHROTIC SYNDROME Loss of epithelial foot processes. > 3.5 g proteinuria, hypoalbuminemia, hyperlipidemia, lipiduria.
NEPHRITIC SYNDROME Hypercellular glomeruli. Hematuria, azotemia, proteinuria (< 3.5 g), oliguria, edema,
HTN.
RAPIDLY PROGRESSIVE Epithelial crescents. Nephritic syndrome, proteinuria, acute renal failure.
GLOMERULONEPHRITIS
Isolated urinary abnormalities Other pathologies. Hematuria and/or proteinuria.
5. IgA nephropathy.
IgA nephropathy is the most common primary glomerular disease, assoc. w/ isolated hematuria / proteinuria (usually
mild); nephrotic syndrome occasional, crescentic RPGN rare. Variants:
(1) Henoch-Schonlein purpura: IgA nephropathy + systemic vasculitis (inflammation of capillaries & small vessels) –
purpuric skin lesions, cramping abdominal pain, intestinal bleeding, vomiting, arthralgia.
(2) Secondary IgA nephropathy: in pts with liver / intestinal disease.
Histo: mesangial hypercellularity (> 3 cells per
mesangial lobule), immunofluorescence shows
intense granular IgA w/ mesangial “Holly leaf”
pattern, EM shows mesangial electron dense
deposits.
Pathogenesis: abnormality of immune regulation w/
↑ IgA production in response to environmental
agents; may also be a defect in IgA itself, giving rise
to autoantibodies against it.
Prognosis: variable; many pts do well for decades, 15 to 40% eventually develop chronic renal failure; often recurs after
renal transplantation.
6. Rapidly progressive glomerulonephritis.
Rapidly progressive GN (RPGN) is characterized by rapidly declining renal function due to severe glomerular injury
nephritic syndrome + acute renal failure.
~ most common histologic feature is crescentic
glomerulonephritis; crescents = proliferation of
parietal epithelial cells of Bowman’s capsule +
macrophages due to spillage of fibrin, etc.
GBM is disrupted  more damage than other
GNs.
Causes of RPGN:
Type I (Anti-GBM) Type II (Immune Complex) Type III (Pauci-Immune)
Primary immunological disorder - Abs to Progression of other Part of a systemic vasculitis.
peptide in collagen IV of GBM (Goodpasture glomerular diseases – ~ LACK of anti-GBM Abs or immune
antigen); may cross-react w/ pulmonary findings similar to other pts complexes. Glomeruli are surrounded by
alveolar BMs  pulmonary hemorrhage. with specific disease + crescents; IF mostly negative.
- most cases are renal limited; Goodpasture rapid acute renal failure . - ANCA-associated, idiopathic (isolated
syndrome = pulmonary hemorrhage + renal ~ often shows crescents. crescentic GN w/o involvement of other
failure. - idiopathic, post- organs – most of these still have serum
 infectious, SLE, IgA ANCA), Wegener’s, polyarteritis nodosa,
nephropathy, and so on. microscopic polyangiitis.

Dx: serum test for anti-GBM Abs.

Tx: plasmapheresis.

Glomerulonephritis II.

* Nephritic syndrome (see above) is characterized by hematuria (RBC casts), proteinuria (mild to moderate - < 3 g),
hypertension (due to renin release), oliguria (due to ↓ GFR), mild edema, and azotemia (due to BUN & Cr retention).
~ Nephritic syndrome is usually post-infectious:
I. Post-Streptococcal GN is characterized by abrupt hematuria, malaise, & fever (1-2 wks after recovery from sore throat).
~ caused by certain strains of group A beta-hemolytic Strep; most commonly seen in children (most recover w/ consrvative
therapy; < 1% develop rapidly progressive GN).
Pathogenesis: may be due to circulating Strep antigen immune complexes, “planted” Strep antigens on GBM, or both;
GBM proteins altered by streptococcal enzymes may also be targeted by the immune system.
Histo: diffuse endothelial & mesangial
hypercellularity & inflammatory cells (neutrophils)
seen in glomeruli + large subepithelial “hump-
shaped” immune complex deposits.
~ IF shows granular IgG and C3 deposits.
II. Non-Streptococcal GN – pathology similar to post-Strep; may be seen w/ bacterial, viral, & parasitic infections.

* Nephrotic syndrome (see above) is characterized by heavy proteinuria (> 3.5 g/day), hypoalbuminemia (< 3 g/dL),
edema (severe, generalized, pitting), hyperlipidemia (altered lipoprotein metabolism), lipiduria, & fatty casts.
- loss of other proteins in the urine leads to ↓ immune response, thrombosis, altered drug dosages, etc.
Cause Clinical Pathogenesis Morphology
Primary Nephrotic Syndrome.
Minimal change MCC of nephrotic Immune dysfunction → Glomeruli are normal; no immune deposits.
disease syndrome in children; cytokine production & In later stages, lipoid nephrosis (lipids in PCT
10-15% in adults. damage to visceral epithelium) is seen.
~ sudden onset; normal epithelial cells of EM shows
BP & GFR; urine shows glomeruli. effacement of
+4 albumin and oval fat ~ may be assoc. w/ epithelial foot
bodies. respiratory infections, processes.
 Dx by renal biopsy. Hodgkin lymphoma
 responds to steroids and T-cell defects.
- good prognosis, esp.
in children.
Focal segmental Most common primary May occur as a primary Morphology similar to minimal change
glomerulosclerosis glomerular disease disease (idiopathic – disease (effacement of foot processes + lipoid
causing nephrotic nephrin or podocin nephrosis) but includes focal (mainly
syndrome. mutations?) or may be juxtamedullary glomeruli) segmental
~ differs from minimal assoc. w/ HIV ( glomerulosclerosis. In later stages, interstitial
change disease w/ collapsing fibrosis may develop.
more frequent glomerulopathy), - IF is mostly negative; may have secondary
hematuria & HTN and heroin abuse, sickle cell deposits (“trapping”) of IgM & C3 complexes
poor response to (poor oxygenation), or in mesangium.
 steroids. obesity (kidney
~ 50% develop renal overload).
failure within 10 yrs. - may be secondary
Prognosis: few event after previous
spontaneous GN, such as IgA
remissions; children do nephropathy.
better than adults;
recurrence (often rapid)
is common even after
renal transplant!
Membranous Immune complex 85% idiopathic Stages: (1) epimembranous deposits  (2)
glomerulonephritis mediated disease w/ (autoimmune); others GBM grows up between deposits forming
complement (C5b-C9) assoc. w/ infection (Hep “spikes”  (3) GBM grows over deposits 
activation  nephrotic B, malaria, syphilis), (4) markedly thickened GBM, some deposits
syndrome or malignancy (melanoma, gone.
proteinuria; sometimes lung & colon tumors),
hematuria, HTN. medication (NSAIDs,
~ relatively indolent Captopril, mercury, gold,
course; poor response Penicillamine), systemic
to corticosteroids. diseases.
~ 60% have persistent Possible etiologies:
proteinuria, 40% (1) In situ IC formation
eventually develop along GBM via Ab
renal failure. reaction against
~ glomerular sclerosis podocyte antigen
 poor prognosis, mild (primary membranous
proteinuria  GN).
favorable prognosis. (2) circulating Ab-Ag
complexes entrapped
in GBM (secondary * “string of pearls” on IF – granular IgG.
membranous GN assoc.
w/ systemic disease).
Nephrotic on top of Nephritic Syndrome.
Membrano- Mixed proteinuria Type I: deposition of Proliferation of mesangium & capillary loops
proliferative (often nephrotic) & circulating Immune (mesangiocapillary GN).
glomerulonephritis hematuria (nephritic). complexes; antigens Type I: hypercellular “lobulated” glomeruli,
~ most common in involved unknown. "double" GBM; sub-endothelial and
adolescents / young ~ excessive mesangial IgG & C3 deposits in granular
adults. complement activation pattern (C1q & C4 may also be seen).
2 types: similar histo; (both classical &
different EM & IF. alternate pathways).
~ Type 1 often Type II: poorly
secondary to infection, understood; evidence
lymphoma, immune of activation of
deficiencies. alternative
- slow but relentless complement pathway;
course; 50% have renal 70% have circulating C3 Type II: hypercellular “lobulated” glomeruli
failure in 10 yrs. nephritic factor. (similar to Type I), C3 deposits in ribbon-like
Tx: immunosuppression pattern on GBM adjacent to but not in dense
not very effective. deposits (lamina densa of GBM and tubular BM
~ recurrence after transformed into thick ribbon-like dense deposit).
transplantation
common but renal
 failure in allograft less
common.

Systemic Nephrotic Syndrome.

Diabetes mellitus * Diabetes is the MCC
of end-stage renal
disease in the U.S.
Amyloidosis
SLE Class V SEE SYSTEMIC GLOMERULONEPHRITIS LECTURE.