Chronic Liver Injury

Causes of Chronic Liver Injury – Three Mechanisms

(1) Hepatocyte destuction – usually by inflammation (disease or autoimmunity); also toxins, virus, or genetic abnormality

Autoimmune – usually affects young women, 10 - 30 years old(women may have more active immune system)

activated lymphocytes destroy hepatocytes (and other tissues too) by antibody-mediated cellular cytotoxicity

autoantibodies often produced against a -actin (smooth muscle)

other possibilities: a -KM1 (present in liver/kidney microsomes) and SLA (soluable liver antigen)

80% of all cases are related to lupus; some autoimmunity possibly due to superantigens from drug metabolism

high dose steroid therapy – can be much better in weeks

Viral – due to hepatitis B, delta, or C (A and E are not chronic) – often subclinical acute infection

in hepatitis B, damage is due to inflammatory response, NOT direct cytotoxicity

nucleocapsid peptides (HBcAg) are presented by MHC-I, leading to CD8+ mediated cell death
chronic is due to partial immune tolerance – impaired T-cells, fail to display or recognize viral or MHC

chronic viral hepatitis does not respond to steroid treatment, but interferon may be used successfully

direct antiviral effects – stimulates cellular RNAses, inhibition of viral entry, inhibition of replication
immunomodulatory effects – enhance CD8+, stimulate NK cells, amplify MHC-I

disease determined by immune reaction to virus – appropriate will eliminate virus with minimal liver damage

too aggressive – fulminant liver failure – eliminate virus at expense of liver
not sufficiently aggressive – viremia – no hepatitis, but virus multiplies unchecked

Drug Induced – caused by many drugs; those with strongest correlation are no longer used

include: oxyphenisatin (laxitive), nitrofurantoin (UTI antibiotic), alphamethyldopa (antihypertensive), dantrolene (smooth muscle relaxer)
many other drugs (e.g., isoniazid, papaverine, acetominophen) might cause hepatitis
alcohol is the cause of 60-70% of cirrhosis

Hemochromatosis – absorb too much iron all life – genetic basis now understood

more often men – women somewhat protected because of menstruation
also: skin bronzing, cardiomyopathy and conduction dissorders, diabetes mellitis (pancreatic), testicular atrophy and arthritis

Wilson’s Disease – too much copper – not enough serum ceruloplasmin (copper-binding), or inactive

accumulates in brain and liver
also: Kayser-Fleischer ring (around iris), neuropsychiatric, cardiomyopathy, Fanconi syndrome (kidney), osteopenia/arthropathy

Alpha-1-antitrypsin deficiency – very common (1/30 Caucasians are heterozygous)

enzyme produced in liver – protects lung from protease (emphysema)
protein is made appropriately, but not exported – can produce neonatal hepatitis and hepatocellular carcinoma

(2) Biliary Outflow Obstruction ("cholestasis") – accumulate bile acids and copper – can be at any point along bile tract

alteration in canilicular membrane and tight junctions, condensation of microfilaments Þ no longer transported

obstruction of bile ducts:

primary biliary cirrhosis (autoimmune – mostly middle-aged women)

primary sclerosing cholangitis (inflammation of ducts)

biliary atresia

pancreatitis (compress bile duct)

Dubin-Johnson Syndrome

viral or alcoholic hepatitis

pregnancy

cholangiocarcinoma,

protoporphyria (liver disease also resulting in severe sunburns)

results in:

ß bilirubin excretion (sometimes causes jaundice)

ß excretion of bile salts (fat malabsorption, deficiency in vitamins A, D, K, and pruritis)

ß cholesterol excretion (xanthomas)

(3) Hepatic Venous Outflow Obstruction – not common; occurs in heart failure or constrictive pericarditis

heart failure

low cardiac output Þ low liver O₂ Þ zone 3 necrosis, reticulin collapse, fibrosis Þ "cardiac cirrhosis"

low right atrium pressure Þ increased hepatic venous pressureÞ sinusoidal distention and hemorrhage

hepatic vein occlusion (Budd-Chiari syndrome) – thrombosis, congenital web, tumor

central vein occlusion (venoocclusive disease) – from chemotherapy, especially with concurrent radiation therapy

also caused by plant alkaloids that are combined in various herbal remedies

Results of Chronic Liver Injury – usually cirrhosis

Cirrhosis is the deposition of excess collagen tissue along with matrix components (proteoglycans and glycoproteins)

continual damage – necrosis replaced by collagenous scar tissue
regenerative hepatocyte nodule surrounded by dense collagenous septa – lose liver architecture (important for function)

hepatocyte projections and capillary fenestrations disappear; dense collagen in Space of Disse – insulate from blood

mostly collagen (types I, II, IV, and V); type I has most crosslinkages, so is degraded slowest and predominates in disease

Ito cells activated during liver damage – get cytokine receptors, actin, etc. – possibly induced by Kuppfer cells

respond to locally produced cytokines (especially PDGF) – produce collagen

Impact of Cirrhosis – high pressure instead of high flow – blood goes around rather than through liver, isolating liver cells

hepatocytes use hepatic artery rather than portal vein for O₂, thus robbing liver of the "first pass" at nutrients

Grading Schemes

Classical Grading System – based upon extent of inflammation

portal triads only: chronic persistent hepatitis (CPH)

portal and periportal regions: chronic active hepatitis (CAH)

entire lobule (acini): chronic lobular hepatitis (CLH)

Modern Grading System – based upon four hitological criteria

(1) periportal or bridging necrosis (1-10)
(2) parenchymal injury(interlobular HC degen/necrosis) (0-4)
(3) portal inflammation (0-4)
(4) also fibrosis (0-4)– used to grade

Histopathological Features

Normally, there is clean connective tissue around the portal triad with a layer of hepatocytes ("limiting plate").

Piecemeal necrosis – inflammation at interface between the lobule and connective tissue of the portal area

piecemeal necrosis can occur even after cirrhosis occurs, producing periportal hepatitis

the portal area broader, becomes fibrotic, bridging – inflammation then becomes fibrous – develop into steatosis

Different forms of hepatitis look superficially similar – non-specific morphology, so history taking is vital for diagnosis

viral hepatitis – fine granular occlusions (cytoplasmic) – viral antigens stain brown with immunoperoxidase

portal triad is main area involved; lymphocyte infiltrate with piecemeal necrosis ("blue polka dot" liver)
bile duct changes, steatosis of hepatocytes

autoimmune hepatitis – extensive bridging necrosis, much inflammation between portal areas, many plamsa cells

inflammatory bile duct disease – portal and bile duct inflammation – bile duct epithelial damage and loss

frequently includes granulomas and secondary bile duct proliferation
primary sclerosing cholangitis – "onion-skin" periductal fibrosis – circular fibers
liver loaded with bile – looks black rather than green; enormous amount of bile histologically (greenish-brown)
staging – 1 (minor portal hepatitis) to 4 (cirrhosis)

hepatic iron overload – stain blue with Prussian blue stain (very clear – do not need microscope)

often accompanied by micronodular cirrhosis – often bile duct damage only if genetic (hemocromatosis)

ferritin and hemosiderin stored in liver lysosomes – liver looks grossly chocolate brown

Fe seen in hepatocytes (especially periportal), less in kruppfer and bile ducts Þ fibrosis micronodular cirrhosis

staging – 1 (pre-scarring iron loading) to 3 (cirrhosis)

Wilson’s disease – accumulation of copper in liver

staging – 1 (mild iron deposits) to 3 (cirrhosis)

Alpha-1-Antitrypsin – synthesis of antitrypsin in liver, but not exported

enormous globules under PAS stain or antiperoxidase
dilated rough and smooth ER

Drug Toxicity – looks like chonic viral hepatitis

steatosis and inflammatory damage – very few get cirrhotic – bridging fibrosis
low doses of methotrexate used for psoriasis and rheumatoid arthritis – stopped just before cirrhosis

Cirrhosis – whole liver transformed into structurally abnormal nodules surrounded by fibrosis

micronodular (<3 mm) or macronodular (>3 mm, can be more than 1 cm) – may be mixed
no lobules architecture visible – little nodules, large amounts of fibrous tissue (collagen)
sometimes inflammation or bile duct proliferatio

Hepatocellular Carcinoma – large N/C ratio, huge amount of fibrosis

large cell vs. small cell displasia – small cell is predominant pathway – NOT same as small cell of lung
may be white, often green or show necrosis/hemorrhage, sometimes pseudoglandular (bile production)
often stain for AFP by immunoperoxidase

Cholangiocarcinoma – cancer of bile ducts

can be extrahepatic or intrahepatic – look like adenocarcinomas

Cirrhosis

the end result of several forms of chronic liver disease—the normal lobular and vascular architecture is destroyed. Cirrhosis is associated with the formation of fibrous septa and regenerating nodules. In such nodules the liver cell plates are more than two cell layers thick and the zonal arrangement of hepatic blood flow is absent. Ito cells switch over to producing collagen because of cytokines and lipid peroxidation.

D P = Q x R with cirrhosis there is Ý portal pressure due to ß blood flow (Q) and Ý resistance (R)

Portal Hypertension – when WHVP exceeds IVC pressure by more than 4 mmHg

Wedge pressure- measured by catherization; a catheter with a balloon isolates a segment of liver. The "Wedge pressure" (WHVP) is measured. The balloon is deflated and the "Free pressure" (FHVP) is measured. The difference is equal to the pressure gradient across the sinusoids(HVPG). WHVP – FHVP = HVPG (Ý HVPG in cirrhosis)

Portal vein pressure may be elevated Pre-sinusoidal (before hepatic sinuses, e.g. Schistosomiasis), Sinusoidal (cirrhosis), or Post-sinusoidal (hepatic vein occlusion)

Collateral circulations – 4 major collateral circulations shunt portal blood from the portal system to the caval system

(1) Esophageal varices – common finding, common site of hemorrhage
(2) Rectum (internal hemorrhoids) – common, rarely hemorrhage
(3) Umbilical vein (Caput Medusea) – rare site of bleeding
(4) Retroperitoneal varices – rare bleeders barring trauma

The mid esophagus drains in the azygous. Esophageal varices are visualized as filling defects in a barium swallow.

Varices can rupture and bleed out (often with arterial like force including pulsations!)

Red Wail Signs – veins on veins that form on large varices.

DOGMA – there has to be a gradient greater than 12 mmHg to bleed

Treatment – protect the airway, nitroglycerine and drugs that reduce mesenteric blood flow, Band ligation via endoscope, TIPS (transjugular intrahepatic portal shunt), endoscopic sclerosing of varices (not used as much anymore)

Acites – most common complication of cirrhosis, Ascites does not develop without portal hypertension

50% prevalence after 10 years with cirrhosis, 50% survival rate at 2 years once ascites develops

at the one year mark, survival is much better with a liver transplant

2 theories on the development of ascites

(1) Classic "Underfill" theory – urinary Na⁺ and H₂O retention after the development of ascites
(2) "Overfill" theory – urinary Na^{+ and}H₂O retention before the development of ascites

hypoalbuminemia – due to chronic liver disease leads to a low plasma oncotic pressure

impaired reabsorption of peritoneal fluid – contributes to the maintenance of ascites

Treatment – Na⁺ restriction, paracenteses, diuretics that block Aldosterone (Loop diuretics aren’t as effective since the elevated Aldosterone level will only reabsorb

he Na⁺ placed in the lumen of the proximal tubule in the distal tubule)

Some causes of acites:

Umbilical Hernia – 35% ulceration, 14% incarceration, 7% rupture

Treatment – control ascites, elective surgery, if ruptures Þ emergency surgery

Hepatic Hydrothorax– due to a direct communication in the diaphragm. (66% right sided / 17% bilateral)

fluid accumulates in the thorax due to communication with the peritoneum. Fluid is ascites like when tested

Treatment – diuretics, needle drainage of thorax, TIPS, or liver transplant

Infection – most serious consequence of ascites Þ will kill the patient

Lymph flow is 10-20 x’s increased with ascites, bacteria in lymph have systemic access, if not opsonized by WBC’s the bacteremia may go into the ascitic fluid and cause Spontaneous Bacterial Peritonitis (SBP)

SBP – 70% one year mortality, frequent reoccurances, MOST SERIOUS COMPLICATION of ascites

Treatment – broad spectrum IV antibiotics (no aminoglycosides because of vulnerable kidneys)

Hepatic Encephalopathy

neuropsychiatric abnormalities in patients with significant liver failure. Hepatocerebral syndromes – ABC’s:

Acute liver failure associated with HE (HE within 8 weeks of liver dysfunction)
Encephalopathy with Bypass
Encephalopathy in Cirrhosis / Chronic liver disease

Diagnosis – identify hepatic dysfunction, identify motor disturbances and/or alterations in mental status, rule out other causes (CNS trauma, septic encephalopathy, drug intoxication, etc), identify and treat precipitating factors (GI bleed, sedative drugs, hypokalemia, alkalosis, uremia, dehydration, constipation, etc).

60-70% of patients with cirrhosis have evidence of subclinical encephalopathy

Modified West Haven HE staging –

0 – no abnormality detected
1 – change in personality, shortened attention, insomnia, arithmetic difficulty
2 – lethargy, monotone voice, loss of time orientation
3 – somnolent but responsive to stimuli
4A – coma, responsive to major stimuli
4B – coma, anesthetized (rate comas on the Glasgow Coma Scale)

Asterixis – a clinical sign of HE, when holding arms out (like "stop" sign) the hands "flap"

On CT scan – HE brains have prominent sulci and ventricles; EEGs have slow, high voltage spikes, MRI’s show manganese deposits.

Pathogenesis – no one knows for sure, commonly thought that toxic neurotoxins produced by bacteria in the colon get into the brain and wreck havoc. (possibly ammonia, benzodiazepine like compounds, and/or GABA)

GABA – opens Cl^-channels to achieve a hyperpolarized state (keeps one from convulsing) // benzodiazepines are in meat and elevated levels have been found in HE patients in comas.

Treatment – supportive for Coma

Stop production of neurotoxins in colon by reducing the time substrate is in the colon or bacteria in colon

Lactulose – a disaccharide that can only be broken down by colonic bacteria Þ diarrhea

Antibiotics – Neomycin or Metronidazole to knock out colonic flora

Hepatorenal Syndrome – unexplained renal failure in patients with severe liver disease

50% survival at 3 weeks, ~ 100% mortality without liver transplant, only a 50% 3 year survival with liver transplant
"functional disorder" probably due to circulating toxins
precipitating factors – severe GI bleed, vigorous diuresis, sepsis, NSAID usage.
diversion of renal blood flow from the cortex to the medulla due to vasoconstriction resulting in a reduced GFR
low urine output, rising blood creatine and nitrogen, and all other causes of renal failure ruled out
Improves without treatment after liver transplant, if kidney is removed and placed in a healthy person it works fine.

clinical features – ascites, hypotension, jaundice

labs – urinary Na⁺ is low (< 10 mEq/L), azotemia

Treatment – restrict Na^{+ and}H₂O, dialysis, TIPS, liver transplant. Vasoconstrictors appear to help