Cirrhosis and Portal Hypertension

Classification:
1)
Micronodular cirrhosis:
- Thick regular septa, small uniform regenerative nodules, involvement of every
hepatic lobule
2)
Macronodular cirrhosis:
- Septa, regenerative nodules varying sizes -> contains irregularly sized
hepatocytes with large nuclei and cell plates of varying thickness
3)
Mixed cirrhosis:
- Regeneration is occuring in micronodular liver -> converting to macronodular
(between the two)
Etiology:
- Viral, autoimmune, drug-induced, cholestatic, metabolic disease
- Alcoholic hepatitis: hepatocyte necrosis, Mallory bodies, neutrophil infiltration,
perivenular inflammation
- Nonalcoholic steatohepatitis (NASH): no alcohol consumption, exclusion of
other causes of hepatic steatosis, unrecognized NASH contributes a lot cases within
cryptogenic cirrhosis
- Chronic Hepatitis C infection: most common cause of chronic liver disease +
indication of liver transplantation in US, identified by serologic assays to Hep C +
molecular assay viral RNA; Hepatitis B: can be identified by HBsAg antigen more
than 4-6 months after initial infection, Hep B viral replication, HBeAg and Hep B viral
DNA -> this can also guide appropriate antiviral therapy
- Autoimmune cause: Primary biliary cirrhosis (fatigue, pruritus, skin
hyperpigmentation not related to jaundice; tested by antimitochondrial antibodies,
elevation of serum cholesterol, hyperbilirubinemia), primary sclerosing cholangitis
(ulcerative colitis, Crohns disease; pruritus, steatorrhea, fat-soluble vitamin
deficiencies, metabolic bone disease; diagnosis by imaging of biliary tree;
complications are common and include biliary strictures, cholangitis, cholelithiasis,
cholangiocarcinoma), autoimmune hepatitis (elevation in serum gamma globulins,
liver biopsy show nonspecific changes such as portal mononuclear cell infiltrate with
characteristic presence of plasma cells; treatment by prednisone with/without
azathioprine)
- Hereditary hemochromatosis: most common metabolic disorder causing
cirrhosis, suspected if patient has skin hyperpigmentation, diabetes mellitus,
pseudogut, cardiomyopathy, hereditary cirrhosis; confirmed by genetic testing, liver
biopsy, assessing response to phlebotomy
Clinical manifestations:
- Fatigue, anorexia, weight loss, jaundice, abdominal pain, peripheral edema,
ascites, GI bleeding, hepatic encephalopathy
- PE findings: spider angiomata, palmar erythema (alteration of sex hormones),
finger clubbing (hypoalbuminemia), white nail bed and Dupuytrens contractures less
well understood, feminization of males, ascites and pleural effusion, portal
hypertension (presence of Cruveilhier-Baumgarten murmur), jaundice (>2-3 mg/dL),
asterixis, fetor hepaticus, malnutrition symptoms (weakness, weight loss, temporal
muscle wasting)
- Resting energy expenditure increase increase, correlate within ascites, low
mean arterial pressure, plasma renin activity

- Abdominal hernia also normal in cirrhosis, HCC (hepatocellular carcinoma)

can occur in all forms of cirrhosis as well (check with serum AFP level), also
associated with increased cardiac output and heart rate, more prone to infections
Lab findings and liver biopsy:
- Mild normocytic normochromic anemia, WBC and platelet reduced, bone
marrow is micronormoblastic, PT prolonged (not respond to Vit K), serum albumin
increased, urobilinogen present, decrease in urinary sodium excretion diminishes
- Normal liver function test do not eliminate possibility of cirrhosis
- Liver biopsy from percutaneous, transjugular, laparoscopic; serologic markers
to help predict presence of cirrhosis without need for liver biopsy; ultrasound
elastography also measure stiffness of liver (elastic shear) to identify advanced
fibrosis and cirrhosis
Hepatic reserve + surgical risk:
- Monoethylglycinexylidide (MEGX) has 80% sensitivity and it loses sensitivity
and specificity if serum bilirubin level rises (interferes with fluorescent readout
system)
- Child-Pugh Score: Predicting surgical risk of intra-abdominal operation of
cirrhotic patients, mortality for class A = 10%, class B = 30%, class C = 75-80%

- MELD: linear regression model by laboratory value (INR, bilirubin level,

creatinine level), MELD below 10 is safe, 10-15 can go with caution, >15 should not
do surgery

Portal Hypertension:
- Portal venous system: 75% of blood, 72% of oxygen supplied to liver
- Cirrhosis increase supply of blood to liver and thus increase portal venous
pressure, a shunt (from tributaries of portal vein) would bring the blood around the
liver and into systemic circulation

- Doppler ultrasound, CT and MRI used evaluate portal vein anatomy and
patency, visceral angiography and portal venography (most accurate, can measure
free hepatic venous pressure and wedged HVP) for further investigation
- 3 types: presinusoidal (portal vein thrombosis), sinusoidal (cirrhosis,
Schistosomiasis), postsinusoidal (hepatic vein thrombosis (Budd-Chiari syndrome))
- Results in: Gastroesophageal varices, splenomegaly, ascites, umbilical vein
recannulation and dilation, anorectal varices, spontaneous shunting between portal
venous system and left renal vein or IVC, but shunts not effective
- Gastroesophageal varices: leading cause of morbidity, administration of betablockers and prophylactic endoscopic surveillance within variceal band ligation to
prevent
- Management: blood resuscitation, vasoactive medication decrease blood flow
- octreotide (somatostatin analog), endoscopy within variceal band ligation
- Failure to control -> Sengstaken-Blakemore tube (high complication rate aspiration, airway obstruction, esophageal perforation), should not exceed 36 hours
to avoid tissue necrosis
- Transjugular Intrahepatic Portosystemic Shunt (TIPS): metallic stent between
intrahepatic branch of portal vein, hepatic vein radicle, high rate of thrombosis and
thus frequent follow-up with repeated dilation or restenting to maintain patency
- Balloon-Occluded Retrograde Transvenous Obliteration (BRTO): catheter
directed through left renal vein into spontaneous shunt
- Surgical shunting: MELD score <15 and not candidates for hepatic
transplantation, limited access to TIPS therapy etc, to reduce portal venous pressure,
maintain hepatic and portal blood flow, avoid high incidence of complicating hepatic
encephalopathy (hepatic reserve determine patient survival)
-

- Sugiura procedure: devascularization of stomach + distal esophagus +

transection of esophagus, splenectomy, truncal vagotomy, pyloroplasty
- Hepatic Transplantation: Cirrhosis, portal hypertension and variceal bleeding
-> hepatic failure; transplantation is only definitive therapy and crucial for long-term

survival, previous performance not affected by endoscopic variceal band ligation,

TIPS, splenorenal or mesocaval shunts, but Eck fistula make hepatic transplantation
technically more difficult and thus is avoided
- Buud-Chiari Syndrome: uncommon congestive hepatopathy due to
obstruction of hepatic venous outflow, 1 in 100,000 incidence; presented with acute
signs and symptoms of abdominal pain, ascites, and hepatomegaly
- Primary BCS: obstructive involves endoluminal venous thrombosis;
Secondary BCS: veins are compressed or invaded by neighbouring lesion outside of
vein
- Risk factors: primary myeloproliferative disorders (essential thrombocythemia
or polycythemia rubra), activated protein C resistance (factor V Leiden mutation),
anticardiolipin antibodies, hyperhomocysteinemia, oral contraceptive use
- Clinically significant BCS -> obstruction of 2 or more major hepatic veins ->
hepatomegaly, liver congestion, right upper quadrant pain; perfusion also decrease,
noninflammatory centrilobular necrosis result
- Most patients go on and develop chronic portal hypertension and ascites,
caudate lobe hypertrophy in 50% cases as closest to IVC, but hypertrophy would
block IVC and thus further obstruction
- Diagnosis: abdominal ultrasonography, CT, MRI, hepatic venography to
determine presence and extent of hepatic thrombosis and IVC pressure
measurements
- Treatment: Systemic anticoagulation, similar to cirrhotic patients, radiologic
and surgical when condition nonresponsive to medical therapy (percutaneous
angioplasty and TIPS, surgical shunts), hepatic transplantation needed at the end
Exocrine Pancreas
- Pancreatic juice: 500-800 mL per day, colorless, odorless, alkaline, isosmotic
- Acinar Cells secrete amylase, protease (trypsinogen, chymotrypsinogen,
elastase, carboxypeptidase A & B, phospholipase), lipase (pancreatic lipase,
phospholipase A2, carboxylic ester hydrolase, cholesterol esterase); centroacinar
and intercalated duct cells secrete water and electrolyte, bicarbonate from carbonic
anhydrase -> secretion of bicarbonate depending on pancreatic secretory rate
(increase of HCO3 from increased secretion)
- Secretin from S cells (more important) + CCK from I cells stimulate
bicarbonate secretion; gastrin and acetylcholine also weak stimulant; somatostatin
and glucagon inhibit exocrine secretion
Chronic Pancreatitis
- Chronic incurable inflammatory disease, multifactoral in nature
- Chronic inflammation -> fibrosis, duct ectasia, acinar atrophy
- Prevalence: 5-40 person per 100,000 population
- Etiology: genetic mutation, alcohol exposure, duct obstruction (trauma,
gallstones, tumors), metabolic diseases (hyperlipidemia, hyperparathyroidism,
autoimmune disease), nutritional (tropical pancreatitis due to ingestion of certain
starches)
- Genetics: PRSS1 (trypsinogen gene -> excess production thus persistent and
uncontrolled proteolytic activity, autodestruction of pancreas), SPINK1 (inflammation-

induced trypsin inhibitor in acinar cells), cystic fibrosis (CFTR channel in functional,
controls alkalinity of pancreatic juice), CLDN2 (secretory dynamics change if
mutated, risk of CP increase especially with alcohol)

- Alcohol: Linear relationship between exposure of alcohol and development of

chronic pancreatitis, development linked with repeated acute inflammation but other
factors also important: alcohol metabolites (acetaldehyde) + oxidant injury result in
local parenchymal injury -> repeated episodes of toxin-induced injury activate
cascade of cytokines -> induce pancreatic stellate cells to cause fibrosis (either
alcohol sensitizes pancreas, or genetic/other factors predispose to direct alcoholrelated injury); alcohol can also interfere with intracellular transport -> colocalization
of digestive enzymes + lysosomal hydrolase in acinar cells -> autodigestion; calcium
complexed to protein plugs -> ductal cell injury and obstruction of secretory system,
promoting inflammatory response
- Cigarette smoking: unknown reasoning, probably accelerate alcoholic
pancreatitis and hereditary pancreatitis (average carcinoma age decrease by about
20 years)
- Hyperparathyroidism: hypercalcemia -> stimulant for pancreatic calcium
secretion + obstructive pancreatopathy
- Hyperlipidemia: important when they receive estrogen replacement therapy,
maybe due to repeated subclinical episodes of acute inflammation
- Presenting signs/symptoms: 1) Midepigastric pain (main left or right upper
quadrant), penetrating through the back, steady and boring but not colicky, persist for
hours or days, exacerbates during eating/drinking alcohol (but maybe relieved by
alcohol followed by more severe recurrence); due to ductal hypertension (initiated by
eating), parenchymal disease or retroperitoneal inflammation (neural involvement),

acute exacerbations in chronic pain (increase in duct pressure or acute

inflammation), thus surgical relief most useful for ductal hypertension; pain may
decrease over period of years, and exocrine/endocrine deficiency would be apparent
(burned out pancreatitis) and that means severe destruction of pancreas; relieve pain
by a) reduce secretion and/or decompress secretory compartment, b) resecting focus
of chronic inflammation, c) interrupting transmission of afferent nerve pulses
- 2) <10% of exocrine capacity -> diarrhea + steatorrhea, in severe
symptomatic chronic pancreatitis, anorexia + nausea may also occur and also
chronic weight loss; lipase deficiency manifest before trypsin deficiency -> exocrine
function reduced also cause bicarbonate secretion to decreases -> duodenal
acidification and further impair nutrient absorption
- 3) Pancreatogenic diabetes: islet comprise 2%, but preferentially conserved
-> tissue loss + replacement by fibrosis -> islet thus smaller than normal, destruction
of glands cause endocrine insufficiency (ie frank diabetes); ketoacidosis + diabetic
nephropathy uncommon, retinopathy and neuropathy same rate with type 1 and 2;
seen due to chronic pancreatitis or surgical resection; type 3c -> deficiency of all 3
islet cell hormones: insulin, glucagon, PP -> insulin therapy difficult (hyperglycemic or
hypoglycemic easy), PP deficiency also correlates within severity of chronic
pancreatitis
- Laboratory studies: 1) pancreatic products in blood (lipase and amylase, PP
test in response to test meal), 2) exocrine function (Lundh test meal, CCK or secretin
stimulation, or measurements of metabolites ie PABA, lipase secretion), 3) imaging
(ERCP, CT, MRCP)
- Prognosis: symptom of pain decrease -> progression of insufficiency
increase, survival decrease within chronic pancreatitis, pancreatic carcinoma also
may result (10-fold greater)

Forward Flow Theory of Portal Hypertension

Evaluation of Liver function

Note that:
- AST:ALT ratio is typically <1 in patients with chronic viral hepatitis and
nonalcoholic fatty liver disease, a number of groups have noted that as cirrhosis
develops, this ratio rises to >1. An AST:ALT ratio >2:1 is suggestive, whereas a ratio
>3:1 is highly suggestive, of alcoholic liver disease.