Chapter 18: Liver Diseases Flashcards
Regeneration of the liver occurs via 2 major mechanims, which are?
1) Proliferation of remaining hepatocytes
2) Repopulation from progenitor cells
Describe the priming, growth factor, and termination phases of hepatocyte proliferation in the regenerating liver?
1) Priming - IL-6 produced by Kupffer cells act on hepatocytes making parenchymal cells competent to receive/respond to GF signals
2) GF phase - factos such as HGF and TGF-α act on primed hepatocytes to stimulate cell metabolism and entrance into cell cycle
3) Termination - hepatocytes return tp quiescence
Which 3 serum enzyme measurements represent a response to disrupted hepatocyte integrity?
- ALT
- AST
- LDH
Serum measurements of which 2 enzymes look for damage to bile canaliculus?
- Serum alkaline phosphatase
- Serum γ-glutamyl transpeptidase (GGT)
Which 2 serum measurements assess hepatocyte metabolism; which is increased in liver disease and which is decreased?
- Serum ammonia –> increased in L.D.
- Aminopyrine breath test (hepatic demethylation) –> decreased in L.D.
Accumulation of fat (steatosis) and bilirubin (cholestasis) in hepatocytes represent _________ (reversible/irreversible) changes
Reversible
What is the predominant mode of hepatocyte death seen in ischemic/hypoxic injury and is a significant part of oxidative stress?
Necrosis
Which cells cluster at sites of hepatocyte injury and mark sites of hepatocyte necrosis?
Macrophages
Councilman bodies are the apoptotic bodies associated with what disease?
Yellow fever
What is the name of the apoptotic bodies seen in diseases such as acute and chronic hepatitis?
Acidophil bodies –> deeply eosinophilic staining
Is stem cell replenishment a significant part of parenchymal repair during hepatocyte regeneration?
- NO
- Hepatocytes are almost stem-cell like in their ability to continue to replicate even in the setting of years of chronic injury
Eventually, in chronic disease the hepatocytes reach replicative capacity (senesence) and stem cell activation occurs in the form of which reaction?
Ductular reactions
What is the principal liver cell type involved in scar deposition?
Hepatic stellate cell
The expression of which receptor by hepatic stellate cells is one of the initial changes during their activation into myofibroblasts?
PDGFR-β
What is seen encircling the surviving, regenerating hepatocytes in the late stages of chronic liver disease and give rise to the diffuse scarring described as cirrhosis?
Fibrous septa
Stellate cells transform into myofibroblasts that when stimulated by ________ can contract
Endothelin-1 (ET-1)
Chemotaxis of activated stellate cells to areas of injury are promoted by which factors?
- PDGF
- Monocyte chemotactic protein-1 (MCP-1)
If the chronic liver injury leading to scar formation is interrupted (i.e., clearance of hepatitis virus infection, cessation of alcohol use), which events occur leading to reversal of scar formation?
Which factor breaks the scars apart?
- Stellate cells stop being activated
- Scars condense –> become more dense and thin
- Metalloproteinases produced by hepatocytes break the scar apart
Acute liver failure (aka fulminant liver failure) is defined as occuring within what time period?
Associated disorders?
Pre-existing liver dysf.?
- Occurs within 26 weeks (6 months) of the initial liver injury
- Associated w/ encephalopathy and coagulopathy
- Absence of pre-existing liver disease
Acute live failure is caused by what type of tisuse injury?
Massive hepatic necrosis
What is the major cause of acute liver failure in the US?
What accounts for the rest of cases?
- Accidental or deliberate OD of Acetaminophen (major cause)
- Autoimmune hepatitis
- Other drugs/toxins
- Acute hepatitis A and B infections
With acetaminophen toxicity, how quicly does the liver failure occur?
Within one week of the onset of sx’s
In chronic inflammation which inflammatory cytokines are produced which act as stimuli for Stellate Cell activation?
- TNF
- Lymphotoxin
- IL-1β
What % of hepatic functional capacity must be lost before hepatic failure ensues?
80-90%
How is the morphology of acute liver failure different in toxic injuries (i.e., acetaminophen) vs. that caused by viral injuries?
Toxic = NO scarring/regeneration due to rapid onset of injury
Viral = scarring and regeneration occur due to slower progression
Diffuse poisoning of liver cells w/o obvious cell death and parenchymal collapse = diffuse microvesicular steatosis, and is usually related to dysfunction of what?
Seen in what settings?
- Mitochondrial dysfunction
- Fatty liver of pregnancy or idiosyncratic rxns to toxins (i.e., valproate or tetracyclin)
Which 3 viruses are most often the cause of fulminant liver failure in the setting of immunodeficiency?
- CMV
- Herpes simplex
- Adenovirus
What is a characteristic sign of Hepatic Encephalopathy?
How does it present?
- Asterixis = nonrhythmic, rapid extension-flexion movements of head and extremities
- Best seen w/ arms held in extension w/ dorsiflexed wrists
Hepatic encephalopathy seen in acute liver failue is due to elevated serum levels of?
Ammonia
Which disorders of coagulopathy may be seen in acute liver failure?
Earliest sign?
- Easy bruising = earliest sign –> can lead to fatal intracranial bleeds
- Liver also removes activated coagulation factors from circulation, and loss of this function –> Disseminated intravascular coagulation
Portal HTN is more common in chronic liver failure, but if it occurs in acute liver failure what are the major clinical consequences?
Where is the obstruction in this setting?
- Extrahepatic obstruction
- Ascites and hepatic encephalopathy
What are the main renal functional abnormalities which are seen in Hepatorenal Syndrome associated w/ Acute Liver Failure?
The syndrome’s onset begins with a drop in what and rising?
- Na+ retention
- Impaired free-water excretion
- Decreased renal perfusion and GFR
*Begins w/ a drop in urine output + rising BUN and creatinine
Diffuse transformation of entire liver into regenerative parenchymal NODULES surrounded by fibrous bands and variable degress of vascular (often portosystemic) shunting describes what?
Cirrhosis
What is the utility of the Child-Pugh classification of cirrhosis?
Helps monitor the decline of patients on the path to chronic liver failure
*Class A (well compensated); Class B (partial comp.); Class C (decompensated)*
How does the progression of chronic liver disease correlate with ductular reactions and when are these rxns most prominent?
- Ductular rxns increase w/ advancing stage of disease
- Most prominent in cirrhosis
The morphology of broad bands of fibrous dense scar, often w/ dilated lymphatic spaces, with less intervening parenchyma is related to the prognosis of chronic liver disease how?
- More likely to progress to portal HTN
- End-stage disease
What is the significance of this photo and to our understanding of the cirrhotic liver?
- Image on left is an active drinker, while the one on the right is after following long-term abstinence
- Shows that regression of fibrosis CAN take place!
How does the jaundice associated w/ chronic liver disease differ from that of acute?
How severe can it get and what is the treatment at the most severe stages?
- Associated w/ pruritus –> itching which can be very intense
- Pt may scratch their skin raw and liver transplantation may be the only relief!
What are the adverse effects of impaired estrogen metabolism and consequent hyperestrogenemia associated w/ chronic liver disease?
- Palmar erythema
- Spider angiomas
- Hypogonadism and Gynecomastia in males
What are 4 of the most clinically significant findings of portal HTN in the setting of cirrhosis?
- Hepatic encephalopathy
- Esophageal varices
- Splenomegaly
- Ascites
What is the dominant intrahepatic cause of portal HTN?
Cirrhosis
What is the morphology of the fluid seen in ascites, composed of?
- Serous fluid w/ <3 g/dL of protein (largely albumin)
- Scant # of mesothelial cells and mononuclear leukocytes
What is a significant consequence which may arise from long-standing ascites?
Seepage of peritoneal fluid thru trans-diaphragmatic lymph producing a hydro-thorax, most often on the RIGHT
What are the 3 mechanism which account for the pathogenesis of ascites?
- Sinusoidal HTN promoted by hypoalbuminemia
- Percolation of hepatic lymph into the peritoneal cavity
- Splanchnic vasodilation and hyperdynamic circulation
What is responsible for massive hematemesis and death in pts with advanced cirrhosis of the liver?
Esophageal varices
Massive splenomegaly associated w/ portal HTN may secondarily induce what hematologic abnormalities?
- Thrombocytopenia –> low platelet count
- Pancytopenia –> low red and white cells + platelets
What is the pathogenesis of Hepatopulmonary Syndrome associated w/ cirrhosis of the liver and portal HTN?
Intrapulmonary vascular dilations –> ↑ blood flow –> ↓ O2 diffusion of blood —> hypoxia (dyspnea that is worse when standing)
Pts experiencing Hepatopulmonary Syndrome will have what symptom?
Dyspnea exacerbated in an upright position
*Poorer prognosis
What are the 2 most common clinical manifestations of Portopulmonary HTN?
1) Dyspnea on exertion
2) Clubbing of the fingers
Which viral hepatitis does NOT cause chronic hepatitis or a carrier state?
Hepatitis A
Which family does Hep A belong to?
DNA or RNA virus?
Enveloped or non-enveloped?
- Picornavirus family
- small, nonenveloped, (+)-strand RNA virus
How is Hep A typically spread?
- Ingestion of contaminated food/water
- Fecal-oral
What is a common cause of sporadic infection and source of outbreaks of Hepatitis A in developed countries?
- Consumption of raw or steamed shellfish, which concentrate the virus from seawater contaminated by human sewage
- Works in food industry may also be a source of outbreaks
Which immune cell appears to play the key role in the hepatocellular injury caused during Hep A and B infection?
CD8+ cytotoxic T cells
Which antibodies against HAV appear with onset of symptoms?
Followed by the appearance of which antibodies, conferring lifelong immunity?
- IgM anti-HAV appear at onset of sx’s
- IgG anti-HAV appear later and confer immunity
Even in the absence of cirrhosis, chronic infection by which hepatitis virus is an important precursor for the development of hepatocellular carcinoma?
Hepatitis B
In high prevalence areas of HBV what is the major mode of transmission?
Transmission during childbirth
What is the most common mode of transmission for HBV in areas with intermediate prevalence and areas with low prevalence?
- Intermediate - horizontal transmission in early childhood, thru minor breaks in skin or mucous membranes
- Low - unprotected sex and IV drug abuse (sharing needles)
Which virus family is HBV a part of?
Describe its morphology (RNA/DNA, envelope, shape)
- Hepadnaviridae fam
- Enveloped, PARTIALLY double-stranded circular DNA
How is the diagnosis of Hepatitis A made?
Detection of serum IgM Abs
What is unique about the replication cycle of HBV?
Mediated by what?
- Contains Pol, which exhibits both DNA polymerase and reverse transcriptase activity
- DNA —> RNA —> DNA
Which “core” protein of HBV stays within hepatocytes and participates in the assembly of complete virions?
HBcAg
Which mature hepatitis virus, when intact, is referred to as the “Dane particle?”
HBV
What can be used for the diagnosis of HBV infection?
- Detection of HBsAg or anti-HBcAg Abs
- PCR for HBV DNA
Which viral antigen associated w/ HBV appears in the blood before the onset of symptoms?
What does the presence of this Ag indicate?
- HBsAg
- Means there is a LIVE virus and infection, either acute, chronic, or carrier
Presence of which antibodies against viral Ags of HBV are indicative of immunity, cure, or no active disease?
Anti-HBsAg –> may persist for life, conferring protection
Persistence of what viral Ag in HBV infection is an important indicator of continued viral replication, infectivity, and probable progression to chronic hepatitis?
HBeAg
Which immunoglobulin is indicative of acute HBV infection and which is indicative of chronic or resolving infection?
- IgM anti-HBcAg = new infection; acute infection
- IgG anti-HBcAg = old infection; chronic infection
What is the best predictor of chronicity in association with HBV infection?
Age at the time of infection
*Younger the age = higher probability of chronicity
What % of patients infected with HBV actually go on to harbor a chronic form of the disease?
Only 5-10%
Appearance of which 3 serum markers in HBV infections indicate active viral replication?
- HBeAg
- HBV-DNA
- DNA pol
Histologically what is the diagnostic hallmark of chronic Hepatitis B infection?
“Ground-glass” hepatocytes w/ ER swollen by HBsAg
Which family of viruses does Hepatitis C belong to?
What type of virus is it (DNA/RNA) and its characteristics?
- Flaviviridae family
- small, enveloped, ssRNA virus
Repeated bouts of hepatic damage is characteristic of HCV infection, due to what factors (i.e., immunity/vaccine?)
- Genomic instability + antigenic variability of the virus
- No vaccine available
- Anti-HCV IgG Abs do NOT confer effective immunity
Persistent infection + chronic hepatitis are the hallmarks of which viral infection?
HCV
Chronic disease occurs in what % of people infected by HCV?
80-90%
How does the clinical course of acute HCV infection differ from that of HBV?
Acute HCV –> often asymptomatic and much milder than HBV
Persistent elevations in what enzymes are characteristic of chronic HCV infection?
How do the levels change?
- Serum aminotransferases
- Levels wax and wane, but almost never become normal
Which testing must be performed to assess viral replication and to confirm the diagnosis of HCV infection?
PCR for HCV RNA
Infection with HCV genotype 3 is unique in its association with what?
- Metabolic syndrome
- Can give rise to insulin resistance and non alcoholic fatty liver disease
Certain polymorphism in what gene are associated with better response to treatment of HCV infection w/ IFN-α and ribavarin?
IL-28B gene
In 90% of individuals with chronic HCV infection circulating _________ persists despite the presence of antibodies
In 90% of individuals with chronic HCV infection circulating HCV RNA persists despite the presence of antibodies
Lymphoid aggregates or fully formed lymphoid follicles are commonly seen assoicated with chronic hepatits by which virus?
Hepatitis C
What is “co-infection” in regards to the Hepatitis D virus?
Results in?
- Follows exposure to serum w/ both HDV and HBV –> HBV must become established first to provide the HBsAg required for matuation of HDV virions
- Results in acute hepatits that is usually self-limited and followed by clearance of both viruses
There is a higher rate of acute hepatic failure following co-infection by HDV and HBV in whom?
IV drug users
Superinfection with HDV occurs how?
Results in what and when?
Chronic carrier of HBV is exposed to HDV resulting in severe hepatitis around 30-50 days later
What are the 2 phases of HBV-HDV superinfection and what occurs in each?
1) Acute: active HDV replication and suppression of HBV w/ high transaminase levels
2) Chronic: HDV replication decreases, HBV replication increases, transferase levels fluctuate, and disease progresses to cirrhosis and sometimes hepatocellular carcinoma
Hepatitis E virus is transmitted how?
Infection primarily occurs in which age groups?
- Enterically transmitted (fecal-oral), water-borne infection
- Primarily young and middle-aged adults
A characteristic feature of HEV infection is the high mortality rate among?
Pregnant woman
Fulminant hepatitis (acute liver failure) is unusual, but is seen primarily with which hepatitis viruses?
- HAV
- HBV
- HDV
*HEV in pregnant women
In some patients with Chronic Hepatitis the only signs are persistent elevations of?
Serum transaminases
Cryoglobulinemia is found in about 35% of pts with what type of hepatits infection?
Chronic hepatitis C
What is the leading cause of morbidity and mortality for HIV-infected patients?
Chronic HBV or HBC infection
What is the defining histological feature of chronic viral hepatitis?
DENSE mononuclear portal infiltration
Most of the parenchymal injury seen in acute hepatitis is seen how morphologically?
- Scant mononuclear infiltrate
- Scattered throughout the hepatic lobule as “spotty necrosis” or lobular hepatitis
In severe acute hepatitis pattern of necrosis is seen and where?
With increasing severity there will be what pattern of necrosis?
- Confluent necrosis of hepatocytes around central veins
- Increasing severity –> central-portal bridging necrosis
Bile duct injury, potentially mimicing primary biliary cirrhosis is prominent in some pts with what type of viral hepatitis?
Hepatitis C
Fatty change of scattered hepatocytes is associated with what type of viral hepatitis?
Hepatitis C, particularly genotype 3
Which organisms most commonly found is SE Asia is notorious for causing a very high rate of cholangiocarcinoma?
Liver flukes (trematodes)
Acute inflammatory response within the intrahepatic biliary tree caused by gut/biliary tree microflora is called?
Ascending cholangitis
Which region is the highest annual incidence of Autoimmune Hepatitis seen in?
Which sex is more often affected?
- White Northern Europeans
- Females
Type 1 autoimmune hepatitis is most often seen in which age group/sex?
Characteristically associated with what 2 antibodies?
- Middle-aged woman
- Antinuclear (ANA) and Anti-smooth muscle actin (SMA)
Type 2 autoimmune hepatitis is most often seen in which age group/sex?
Characteristically associated with what antibody?
What does this antibody attack?
- Children and Teenagers
- Anti-liver kidney microsome-1 (anti-LKM1) –> attack CYP2D6
What is the most prominent and characteristic component of the inflammatory infiltrate associated with Autoimmune Hepatitis?
Plasma cells
Hepatocyte “rosettes” in areas of marked activity are a characteristic of which disease?
Autoimmune Hepatitis
Very severe hepatocyte injury with widespread confluent necrosis, but little scarring, represents which stage of Autoimmune Hepatitis?
First sign of disease = symptomatic acute hepatitis
In general, prognosis of Autoimmune Hepatitis is better in which age group?
Better prognosis in adults
What is the most common cause of acute liver failure necessitating transplantation in the US?
Acetaminophen
Is acetaminophen itself toxic and which area of hepatocytes is injured first?
Describe the progression to acute hepatic failure, what is the last zone to be injured?
- Toxic agent = metabolite produced by CYP450 in the acinus Zone 3 hepatocytes
- Zone 2 takes over metabolic function, in turn becoming injured
- Severe OD, zone of injury extends to periportal hepatocytes –> acute hepatic failure
This pattern of hepatocyte injury is characteristic of which toxicity?
- Acetaminophen toxicity
- Confluent necrosis seen in perivenular region (zone 3)
“Microvesicular steatosis” (diffuse small droplet fat) is a morphological finding associated with toxicity by which agent?
Which syndrome specifically?
Aspirin (in Reye syndrome)
Bland hepatocellular cholestasis, without inflammation, is characteristic of toxicity due to what agent?
Anabolic streroids
*Also OC’s
Blood-filled cavities, not lined by endothelial cells, knows as Peliosis hepatitis is associated with toxicitiy by which agent?
Anabolic steroids
Which 2 agents are associated with Hepatocellular Adenoma?
- Oral contraceptives
- Anabolic steroids
Which 2 agents are assoicated witn Angiosarcoma of the liver?
- Thorotrast
- Vinyl Choride
Which 2 agents are associated with Hepatocellular Carcinoma?
- Alcohol
- Thorotrast
Which agent is associated with Cholangiocarcinoma?
Thorotrast
Can Hepatic Steatosis (Fatty Liver) associated with alcohol intake be reversed?
Completely reversible with abstinence from alcohol
Alcoholic (Steato-) Hepatitis is characterized by what 3 morphological findings?
- Hepatocyte swelling + necrosis = “Ballooning”
- Mallory-Denk bodies: clumped, amorphous, eosinophilic material in ballooned hepatocytes
- Neutrophilic rxn: accumulate around degenerating hepatocytes
What are Mallory-Denk bodies made up of?
Which diseases of the liver are they found in?
- Tangled/disrupted intermediate filaments (i.e., keratin) + ubiquitin
- Alcoholic Hepatitis, Non-alcoholic liver disease, and Wilson disease
Scarring/fibrosis seen in Alcoholic Steatofibrosis characteristically follows what type of pattern?
Chicken wire fence pattern
Continual subdivision of established nodules by new webs of, perisinusoidal scarring leads to a classic micronodular cirrhosis known as?
Associated with what stage of alcoholic liver disease?
Lannec cirrhosis
*First described for end-stage alcoholic liver disease
Which variant of ALDH is found in 50% of Asians, has a very low activity, and those homozygous for this variant are unable to oxidize acetaldehyde (i.e., alcohol intolerance)?
ALDH*2
*Sx’s = upper body flushing, nausea, and lethargy
Which serum liver enzyme elevations are unique to alcoholic liver disease and can be helpful in a diff. dx of chronic liver injury when adequate hx is not available?
AST > ALT (2:1 ratio)
Hepatomegaly w/ a mild elevation of serum bilirubin and alkaline phosphate levels is characteristic of which form/phase of alcoholic liver disease?
Hepatic Steatosis (fatty liver)
↑ AST/ALT, ↑ Alkaline phosphatase, decreased proteins (globulins, albumin, and clotting factors), and anemia, are common findings in which form/phase of alcoholic liver disease?
Alcoholic cirrhosis
The most common acquired metabolic disorder of the liver is?
Non-alcoholic fatty liver disease (NAFLD)
What is the most common cause of chronic liver disease in the US?
NAFLD
The WHO criteria for Metabolic Syndrome requires at least one of which 4 conditions?
And at least two of which 4 conditions?
One of:
- DM or impaired glucose toleranceorimpaired fasting glucose or insulin resistance
Two of:
- BP >140/90 or Dyslipidemia or Central obesity or Microalbuminuria
NAFLD is found to increase the risk for what malignancy?
May do so even in the absence of?
- Hepatocellular carcinoma
- Often in the absence of significant scarring
The level of activity in which pathway correlates with the stage of fibrosis in NAFLD?
This pathway activates which cells?
Hedgehog signaling pathway –> activates Stellate cells
NASH vs. Alcoholic Hepaitis almost completely overlap histologically, how can they be differentiated?
- NASH = MORE prominent mononuclear cells; LESS prominent Mallory-Denk bodies
- AH = more neutrophils
>90% of previously described “cryptogenic cirrhosis” (i.e., cirrhosis of unknown cause) is now thought to represent what?
“Burned out” NAFLD
How does the morphology of pediatric NAFLD differ significantly from the adult version?
i.e., type of steatosis, fibrosis, and inflammatory infiltrate
- More DIFFUSE steatosis + PORTAL fibrosis
- Portal and parenchymal mononuclear infiltration, rather than parenchymal neutrophils
What is the 2 hit model for the pathogenesis of NAFLD and how do insulin resistance and oxidative injury play a role?
- Insulin resistance –> hepatic steatosis
- Hepatocellular oxidative injury —> liver cell necrosis and inflammatory rxns to it
What is the clinical presentation of NAFLD/NASH most often related to?
Signs and symptoms of the underlying metabolic syndrome, like insulin resistance and DM
Due to the association of NASH w/ metabolic syndrome what is a frequent cause of death in these patients?
Cardiovascular disease
Which 3 characteristics/findings are common to fully developed cases of severe iron overload (hematochromatosis)?
1) Micronodular cirrhosis in ALL patients
2) DM in 75-80% of pts
3) Abnormal skin pigmentation in 75-80% of pts
In which decades do symptoms of hereditary hemochromatosis usually appear?
More often affects which sex?
- 4th to 5th decades in MEN and LATER in women due to menstrual bleeding counterbalancing the overload
- Men:Women (5 to 7:1)
What 3 mechanisms contribute to the liver injury produced by excess iron being directly toxic to tissues?
1) Lipid peroxidation via iron-catalyzed free radical rxns
2) Stimulation of collagen formation by activation of stellate cells
3) Interaction of ROS + iron w/ DNA –> lethal cell injury
Main regulator of iron absorption is the protein ________, encoded by the gene ________ and secreted by the _________
Main regulator of iron absorption is the protein hepcidin, encoded by the gene HAMP and secreted by the liver
The adult form of hemochromatosis is almost always causes by a mutation in which gene?
Located on what chromosome?
- HFE
- Chromosome 6
The most common HFE mutation is a substitution of what AA’s at which AA?
Cysteine-to-tyrosine substitution at AA 282 –> C282Y
The C282Y mutation of the HFE gene causing hemochromatosis is largely confined to which population of people?
White populations of European origin
Is the direct toxic injury produced by iron on hepatocytes and other cells reversible?
Yes, if removed before they are fatally injured
What is seen morphologically in both the early and late stages of the deposition of hemosiderin in the liver associated with severe hemochromatosis?
How does the size of the liver change as well?
- Early: golden-brown hemosiderin granules in cytoplasm of periportal hepatocytes, which stain Prussian blue
- Hepatomegaly due to accumulation
- Late: dark brown to black parenchyma due to overwhelming Fe
- Small, shrunken liver as fibrous septa develop
What is seen morphologically in the heart of severe hemochromatosis?
- Often enlarged
- Hemosiderin in myocardial fibers –> brown myocardium
What is the characteristic color of the skin in someone with severe hemochromatosis?
This color is due to increased what?
Slate-gray color –> increased epidermal melanin production
What are 2 complications of the joints that can arise with severe hemochromatosis?
Cause of each?
- Hemosiderin deposit in synovial joints –> acute synovitis
- Calcium pyrophosphate damage to articular cartilage –> pseudogout (disabling polyarthritis)
Derangement of the HPA axis associated with severe hemochromatosis may cause?
Testes to be small and atrophic
What is the classic tetrad of clinical findings associated w/ hemochromatosis?
- Cirrhosis w/ Hepatomegaly –> abdominal pain
- Abnormal skin pigmentation
- DM from deranged glucose homeostasis
- Cardiac dysfunction (arrhythmias, cardiomyopathy)
Patients with what metabolic liver disease have a 200-fold greater risk of developing hepatocellular carcinoma?
Hemochromatosis
Does treatment of the iron overload in hemochromatosis remove the risk of cancer?
Not fully due to the DNA alterations that occur prior to the time of dx and tx
Screening of whom for hemachromatosis is important?
Family members of probands (the 1st person in a family to have the disease)
Neonatal hemochromatosis (aka congenital hemochromatosis) manifests how and when does it occur?
Which biopsy is needed for the correct diagnosis?
- Severe liver disease occuring in utero
- Extrahepatic hemosiderin deposition, detected by buccal biopsy
Which treatment is utilized to deplete tissue iron stores in pts with hemochromatosis and generally leads to a normal life expectancy?
Phlebotomy
What is the most common cause of secondary (or acquired) hemochromatosis?
Disorders associated with this?
- Disorders associated w/ ineffective erythropoiesis
- i.e., β-thalassemia, Sideroblastic Anemia, and Pyruvate kinase deficiency
*Excess iron results from transfusions, and increased absorption
What is the inheritance pattern of Wilson Disease?
Which gene is mutated and on what chromosome?
- Autosomal recessive
- ATP7B gene on chromosome 13
*Majority of patients are compound heterozygotes w/ different mutations on each ATPB7 allele
Deficiency in the ATPB7 protein associated with Wilson Disease causes what 3 changes that lead to the accumulation of copper?
1) Decreases copper transport into bile
2) Impairs copper incorporation into ceruloplasmin
3) Inhibits ceruloplasmin secretion into blood
By which 3 mechanisms does the accumulated copper in Wilson Disease cause toxic liver injury?
1) Promotes formation of free radicals by the Fenton rxn
2) Binds sulfhydryl groups of cellular proteins
3) Displaces other metals from hepatic metalloenzymes
Excess copper in Wilson Disease can often be demonstrated by using what special stains?
- Rhodamine stain for copper
- Orcein stain for copper-associated protein
Which morphological changes and effects does the excess copper in Wilson disease have on the liver?
**Describe the different states the liver may be in depending on the severity and time frame of the disease**
- Fatty change (steatosis) w/ focal necrosis
- Possible acute, fulminant hepatitis (mimics viral form)
- Chronic hepatitis: inflammation, hepatocyte necrosis, and steatohepatitis (w/ hepatocyte ballooning and Mallory-Denk bodies)
Toxic injury to the brain associated with Wilson Disease primarily affects which area?
Basal ganglia, primarily the putamen, which shows atrophy and even cavitation
The biochemical diagnosis of Wilson Disease is based on which 3 criteria?
Which is the most sensitive and accurate?
Which is the most specific?
1) Decrease in serum Ceruloplasmin
2) Increase in hepatic Cu content = MOST sensitive/accurate
3) Increased urinary excretion of Cu = MOST specific
Due to the toxicity of copper to red cell membranes what complication may arise in Wilson Disease?
Hemolytic anemia
What is the inheritance pattern of α1-antitrypsin deficiency?
Which chromosome is the mutated gene located on?
- Autosomal recessive
- Chromosome 14
What is the normal function of α1-antitrypsin?
Normally acts on?
Inhibition of proteases:
- Neutrophil elastase**
- Cathepsin G
- Proteinase 3
α1-antitrypsin deficiency leads to the development of what 2 main disorders?
- Pulmonary emphysema
- Liver disease
Which genotype of α1AT is the most common type seen in normal individuals (aka the “wild type”)?
Which is the most common clinically significant mutation/genotype?
How does homozygous and heterozygous expression of the mutated phenotype affect levels of α1AT?
- PiMM = “wild type” (Pi = protease inhibitor, MM = genotype of healthy people’s 2 alleles)
- Most common mutated genotype = PiZ
- Homozygotes for PiZZ protein have α1AT levels only 10% of normal
- Codominant expression and PiMZ heterozygotes have intermediate levels of α1AT
What is the most commonly diagnosed inherited hepatic disorder in infants and children?
α1-antitrypsin deficiency
The pathogenesis of α1AT deficiency is due to abnormal migration of the α1AT-Z polypetide where?
Accumulates where and creates which response?
- Defective migration of protein from ER —> Golgi
- Accumulates in the ER —> ER stress –> Unfolded protein response –> apoptosis
Which disorder is characterized by the presence of round-to-oval cytoplasmic globular inclusions in hepatocytes, which are strongly PAS-positive and stain magenta?
α1AT deficiency
Which % of adults with the PiZZ genotype will develop hepatocellular carcinoma?
2-3%; usually, but not always, in the setting of cirrhosis
What are the clinical features of α1AT deficiency in some neonates?
Adolescence?
- Neonatal hepatitis w/ cholestatic jaundice (10-20% of affected)
- Adolescence = hepatitis; cirrhosis; or pulmonary disease
