Chronic Liver Disease

Dr. Mahmoud Ali

Autoimmune hepatitis
Is a chronic hepatitis of unknown etiology characterized by continuing hepatocellular necrosis and inflammation, usually with fibrosis, which can progress to cirrhosis and liver failure. It is characterized by autoimmune features, hyperglobulinemia and the presence of circulating autoantibodies.

when untreated, may have a 6-month mortality of as high as 40%. Natural history of treated 10 years survival is 80%

a classification of autoimmune hepatitis based upon circulating autoantibodies

It should be noted, however, that there is little evidence to support a role for these antibodies in the pathogenesis of this disorder.

Classification
Type 1 classic) Autoantibodies Antinuclear Anti-smooth muscle Anti-actin Anti-soluble liver/ liver pancreas antigen (Anti-SLA/LP) Atypical pANCA Antimitochondrial Type 2 Antibodies Anti-LKM-1 Anti-liver cytosol -1 (Anti-LC1) 2008 UpToDate

categories of AIH
Type I autoimmune hepatitis Is the classic syndrome occurring in young women, Associated with marked hyperglobulinemia, Circulating ANAs, HLA-DR3 or HLA-DR4. Also associated with type I autoimmune hepatitis are auto-antibodies against actin as well as atypical pANCA.

Type II autoimmune hepatitis

often seen in children, more common in Mediterranean populations, Linked to HLA-DRB1 and HLA-DQB1 haplotypes, is associated with anti-LKM1. not with ANA Abs against liver cytosol (anti-liver cytosol 1).

This is the same anti-LKM seen in some patients with chronic hepatitis C Anti-LKM2 is seen in drug-induced hepatitis, anti-LKM3 is seen in patients with chronic hepatitis D.

type III autoimmune hepatitis

have circulating antibodies to soluble liver antigen/liver pancreas antigen. Negative ANA and anti-LKM1

occurring in young women,

have clinical features similar to but more severe than, those of patients with type I.
Whether type III autoimmune hepatitis actually represents a distinct category or is part of the spectrum of type I autoimmune hepatitis remains controversial, and this subcategory has not been adopted by a consensus of international experts.

Pathogenesis of autoimmune hepatitis

in a genetically predisposed individual, an environmental agent can trigger a cirrhosisproducing autoimmune pathogenic process. Thought to involve the antigen, the major histocompatibility complex (MHC), and the T cell receptor (TCR). Viruses and drugs have been suggested as triggering agents but the nature of relevant antigens is still undefined.

Pathogenesis
The weight of evidence suggests that the progressive liver injury in AIH is the result of a cell-mediated immunologic attack directed against liver cells.

Most of the evidence supports a central role for an alteration in T cell function, although abnormalities in B cell function also may be important.

Evidence of autoimmunity
1- Histopathologic lesions are composed predominantly of cytotoxic T cells and plasma cells. 2- circulating autoantibodies.

3- Associated autoimmune disorderssuch as thyroiditis, rheumatoid arthritis, autoimmune hemolytic anemia, ulcerative colitis, membranoproliferative glomerulonephritis, juvenile diabetes mellitus, celiac disease, and Sjgren's syndrome increased frequency in their patients relatives.

4- histocompatibility haplotypes associated with autoimmune diseases, such as HLA-B1, -B8, DR3, and -DR4 as well as extended haplotype DRB1 alleles, (5) this type of chronic hepatitis is responsive to glucocorticoid/immunosuppressive therapy,

Genetic predispositions
HLA determinants In Caucasions, classical (type 1) AIH is strongly associated with HLA-DR3 & HLA-DR4 serotype HLA-DR3- associated disease is more commonly found in the early-onset, severe form of disease (often occurring in girls and young women).

HLA-DR4 is more common in Caucasians with late-onset disease and appears to be associated with a higher incidence of extrahepatic manifestations and a better response to corticosteroids Type 2 disease is associated with HLA-DRB1*03 and DQB1*0201 alleles.

TRIGGERING
Remains poorly defined. The presumed environmental triggering agent(s) important in autoimmune hepatitis are unknown, but may involve viruses and drugs. There is some evidence implicating measles virus, hepatitis viruses and Epstein-Barr virus as initiators of disease

A few drugs induce hepatocellular injury that mimics autoimmune hepatitis. These include methyldopa, nitrofurantoin, diclofenac, minocycline, and possibly statins interferon may unmask or induce autoimmunity

Criteria
Major Not essintial

Hypergamaglubulinaemia- IgG Personal or FHx of Autoimmune disease Positive Antibodies Fluctuating course Negative Viruses Arthralgia Portal hepatitis on biopsy HLA DR3 or DR4

clinical features
The onset may be insidious or abrupt; the disease may present initially like, acute or chronic viral hepatitis

distinct features.
Predominantly young to middle-aged women. Fatigue, Commonest malaise, anorexia, amenorrhea, acne, arthralgias, jaundice are common.

Occasionally arthritis, maculopapular eruptions (including cutaneous vasculitis) erythema nodosum, Colitis pleurisy, pericarditis,

sicca syndrome (keratoconjunctivitis, xerostomia) anemia, azotemia, Complications of cirrhosis, such as ascites and edema, hypoalbuminemia, encephalopathy, hypersplenism, coagulopathy, or variceal bleeding may be the PC.

course of AIH
may be variable. mild disease or limited histologic lesions (e.g., piecemeal necrosis without bridging), The natural history of mild disease is variable, often accentuated by spontaneous remissions and exacerbations progression to cirrhosis is limited.

Severe symptomatic AIH

aminotransferase levels >10 times normal, marked hyperglobulinemia, "aggressive" histologic lesionsbridging necrosis or multilobular collapse, cirrhosis), The 6-month mortality without therapy 40%. accounts for only 20% of cases;.

poor prognostic signs

Failure of the bilirubin to improve after 2 weeks of therapy. Histologically multilobular collapse at the time of presentation

Death may result from Hepatic failure, Hepatic coma, Complications of cirrhosis Intercurrent infection. HCC may be a late complication

Laboratory features
Serum AST and ALT levels are increased and fluctuate in the range of 1001000 units. may not correlate with the clinical severity or istopathologic features in individual cases. In severe cases, the serum bilirubin level is moderately elevated. Serum alkaline phosphatase levels may be moderately elevated or near normal.

marked elevations of alkaline phosphatase is a feature of overlap of AIH with PBC. prothrombin time prolonged during active phases or in advance disease. Hypoalbuminemia occurs in patients with very active or advanced disease

Autoantibodies
marked hyperglobulinemia (>2.5 g/dL) is
common in autoimmune hepatitis.

High-titer circulating ANAs.

Rheumatoid factor is common as well. ASMAbs- are less specific, seen just as frequently in chronic viral hepatitis( c ).

Factors that weigh in favor of the diagnosis include

Female gender Predominant aminotransferase elevation Presence and level of globulin elevation Presence of autoantibodies & other autoimmune diseases characteristic histologic features (interface hepatitis, plasma cells, rosettes) HLA DR3 or DR4 markers; and response to treatment

Against the diagnosis

predominant alkaline phosphatase elevation, AMAs- mitochondrial antibodies, markers of viral hepatitis, history of hepatotoxic drugs or excessive alcohol, Histologic evidence of bile duct injury, features of fatty infiltration, iron overload, or viral inclusions

Primary Biliary Cirrhosis

Incidence - 100200 individuals per million, Strong female preponderance Median age - 50 years at the time of diagnosis. The cause of PBC is unknown. it is characterized by portal inflammation and necrosis of cholangiocytes in small and medium-sized bile ducts.

PBC
Cholestatic features prevail, High ALP & GGT. Elevated bilirubin level Antimitochondrial antibodies (AMA) are present in about 90%

These autoantibodies recognize intermitochondrial membrane proteins that are enzymes of the pyruvate dehydrogenase complex (PDC) These autoantibodies are not pathogenic but rather are useful markers for making a diagnosis of PBC.

Histopathologic
The chronic destructive nonsuppurative cholangitis earliest lesion and is a necrotizing inflammatory process of the portal tracts. Medium and small bile ducts are infiltrated with lymphocytes and undergo duct destruction. Mild fibrosis and sometimes bile stasis can occur.

With progression, the inflammatory infiltrate becomes less prominent, but the number of bile ducts is reduced and there is proliferation of smaller bile ductules. Increased fibrosis ensues with the expansion of periportal fibrosis to bridging fibrosis. Finally, cirrhosis, which may be micronodular or macronodular, develops

Clinical Features
asymptomatic. Fatigue Pruritus is seen in approximately 50% of patients at the time of diagnosis It may be intermittent and usually is most bothersome in the evening. Pruritus that presents prior to the development of jaundice indicates severe disease and a poor prognosis .

Physical examination.
Jaundice. complications of chronic liver disease including hepatomegaly, splenomegaly, ascites, and edema. Other features that are unique to PBC include hyperpigmentation,

Hyperpigmentation is evident on the trunk and the arms and is seen in areas of exfoliation and lichenification associated with progressive scratching related to the pruritus. xanthelasma, and xanthomata, which are related to the altered cholesterol metabolism seen in this disease. Bone pain resulting from osteopenia or osteoporosis is occasionally seen at the time of diagnosis

Laboratory Findings
show cholestatic pattern elevation glutamyl transpeptidase alkaline phosphatase (ALP) mild elevations in aminotransferases (ALT and AST). Immunoglobulins, particularly IgM, are typically increased. Hyperbilirubinemia usually is seen once cirrhosis has developed.

overlap" syndrome
Thrombocytopenia, leukopenia, and anemia may be seen in patients with portal hypertension and hypersplenism. Up to 10% of patients with characteristic PBC will have features of AIH as well and are defined as having "overlap" syndrome.

Diagnosis
PBC should be considered in a middle-aged women with chronic cholestatic liver enzyme abnormalities. AMA testing may be negative, and it should be remembered that as many as 10% of patients with PBC may be AMA-negative. Liver biopsy is most important in this setting of AMA-negative PBC. In patients who are AMA-negative with cholestatic liver enzymes, PSC should be ruled out by way of cholangiography

Primary Sclerosing Cholangitis

PSC is a chronic cholestatic syndrome of unknown cause that is characterized by diffuse inflammation and fibrosis involving the entire biliary tree, resulting in chronic cholestasis

This pathologic process ultimately results in obliteration of both the intra- and extrahepatic biliary tree, leading to biliary cirrhosis, portal hypertension, and liver failure.

Primary Sclerosing Cholangitis

The cause remains unknown despite extensive investigation into various mechanisms related to bacterial and viral infections, toxins, genetic predisposition, and immunologic mechanisms, all of which have been postulated to contribute to the pathogenesis and progression of this syndrome

Pathologic changes
Bile duct proliferation as well as ductopenia and fibrous cholangitis (pericholangitis) & periductal fibrosis . Oftentimes, biopsy changes are not pathognomonic, & establishing the diagnosis of PSC must involve imaging of the biliary tree. biliary cirrhosis is the final end-stage.

Clinical Features
Cholestatic liver disease. Fatigue, profound and nonspecific (as in PBC) pruritus, can be debilitating and is related to the cholestasis The severity of pruritus does not correlate with the severity of the disease steatorrhea, deficiencies of fat-soluble vitamins, Metabolic bone disease

Laboratory Findings
Most patients have at least a two-fold increase in ALP may have elevated aminotransferases as well. Albumin levels may be decreased, prothrombin times are prolonged Some degree of correction of a prolonged prothrombin time may occur with parenteral vitamin K. perinuclear antineutrophil cytoplasmic antibody (P-ANCA) is positive in about 65% of patients with PSC

Overlap syndrome (PSC and AIH)

Aminotransferase elevations greater than five times the upper limit of normal with features of AIH on biopsy. Autoantibodies are frequently positive in patients with the overlap syndrome but are typically negative in patients who only have PSC.

PSC & UC
Over 50% of patients with PSC also have ulcerative colitis (UC); accordingly, once a diagnosis of PSC is established, colonoscopy should be performed looking for evidence of UC

PSC Diagnosis
The definitive diagnosis of requires cholangiographic imaging.

MRI with magnetic resonance cholangiopancreatography (MRCP) has been utilized as the imaging technique of choice for initial evaluation.

Once patients are screened in this manner, (ERCP) should be performed to be certain whether or not a dominant stricture is present. Typical cholangiographic findings in PSC are multifocal stricturing and beading involving both the intrahepatic and extrahepatic biliary tree.

Cardiac Cirrhosis
Patients with long-standing right-sided congestive heart failure may develop chronic liver injury and cardiac cirrhosis. long-term right-sided heart failure, leads to elevated venous pressure transmitted via the inferior vena cava and hepatic veins to the sinusoids of the liver, which become dilated and engorged with blood.

Etiology and Pathology

The liver becomes enlarged and swollen, and with long-term passive congestion and relative ischemia due to poor circulation, centrilobular hepatocytes can become necrotic, leading to pericentral fibrosis. This fibrotic pattern can extend to the periphery of the lobule outward until a unique pattern of fibrosis causing cirrhosis can occur

Clinical Features
Patients typically have signs of congestive heart failure Enlarged firm liver on physical examination. ALP levels are characteristically elevated, and aminotransferases may be normal or slightly increased with AST usually higher than ALT. It is unlikely that patients will develop variceal hemorrhage or encephalopathy

Diagnosis
The diagnosis is usually made in someone with clear-cut cardiac disease who has an elevated ALP and an enlarged liver.

Other Types of Cirrhosis

These include inherited metabolic liver diseases hemochromatosis, Wilson's disease Alfa-1-antitrypsin deficiency cystic fibrosis

For all of these disorders, the manifestations of cirrhosis are similar.

Hemochromatosis
is an AR inherited disorder of exesssive iron absorption leading to deposition in several organs and organs failure. The genetic defect in 90 % of cases is a Homozygosity for a single base mutation ( Cystine to Tyresine in C282Y location) in the HFE gene on Ch 6 Recently identified peptide Hepcidin is thought to control Iron absorption. But its abnormalities seen only in few cases.

HH
frequency of hemochromatosis is relatively common, with genetic susceptibility occurring in 1 in 250 individuals, < 5% of those patients who are genotypically susceptible will go on to develop severe liver disease.

Symptoms starts at 40-50 years Later in females. Early symptoms are non-specific: Fatigue Arthralgia Loss of libido Amenorrhea Pigmentation- dusky discoloration is common.

In Advanced cases DM CMP and Arhythmias. ( CHF) Anterior pituitary failure Cirrhosis, liver failure, Hepatocellular cancer- HCC significantly increase risk 200 folds.

Diagnosis
serum iron studies showing an elevated transferrin saturation > 55% in 90% of cases Elevated ferritin level. mutation HFE abnormalities identified by genetic analysis. MRI

Wilson's disease
Is an AR inherited disorder of copper homeostasis with failure to excrete excess amounts of copper, leading to an accumulation in the liver , basal ganglia and iris. Mutation in ATP7B gene on Ch13 leads to failure of coorperation of copper into caeruloplasmin within the hepatocytes and its unable to execreate copper effeciently into bile uncommon, affecting 1 in 30,000 individuals.

PC
Wilson's disease typically affects adolescents and young adults. Asymptomatic Hepatomegaly Acute Hepatitis Fulminant Hepatitis Chronic Hepatitis with CLD

Extrahepatic manifestation
Kayser Fleischers ring and Sunflower cataract NeurologicalTremor, Chorea, Dystonia, poor coordination, Parkinsonism, PsychiatricDepression, neurosis, antisocial behavior emotional liability, poor memory and concentration.

Extrahepatic manifestation
Arthritis, arthralgia Pseudogout Non-immune haemolytic anaemia Fanconi syndrome with RTA2- infiltration renal tubules. Cardiac Arrhythmias Hypo-parathyroidism No risk of malignancy

Diagnosis
Ceruloplasmin levels- low 24-hour urine copper levels elevated Serum copperLow, high or normal. typical physical examination findings, including Kayser-Fleischer corneal rings, and characteristic liver biopsy findings.

AT deficiency
Alfa 1 anti-trypsin ia a protiese inhibitor( Pi) synthesised in the liver during acute phase response, which inhibits neutrophil elastase. Concentration > 40% requered for heath. Low level of Pi is determined by the Genotype Normal is Pi MM genotype AT defeciency develop clinically when < 15%.

Homozygus patients has PiZZ genotype activity < 10% Other Genotypes and % of activity Pi MS 80% PiMZ 60% Pi SS 60% Pi SZ 40%

Diagnosis
ZZ genotype - greatest risk for developing CLD But only about 1020% of such individuals will develop chronic liver disease. Diagnosis determining AT levels and genotype. The only effective treatment is liver transplantation, which is curative as it leads to genotype change.