Chapter 18: Liver Diseases Flashcards
1
Q
Regeneration of the liver occurs via 2 major mechanims, which are?
A
1) Proliferation of remaining hepatocytes
2) Repopulation from progenitor cells
2
Q
Describe the priming, growth factor, and termination phases of hepatocyte proliferation in the regenerating liver?
A
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
3
Q
Which 3 serum enzyme measurements represent a response to disrupted hepatocyte integrity?
A
- ALT
- AST
- LDH
4
Q
Serum measurements of which 2 enzymes look for damage to bile canaliculus?
A
- Serum alkaline phosphatase
- Serum γ-glutamyl transpeptidase (GGT)
5
Q
Which 2 serum measurements assess hepatocyte metabolism; which is increased in liver disease and which is decreased?
A
- Serum ammonia –> increased in L.D.
- Aminopyrine breath test (hepatic demethylation) –> decreased in L.D.
6
Q
Accumulation of fat (steatosis) and bilirubin (cholestasis) in hepatocytes represent _________ (reversible/irreversible) changes
A
Reversible
7
Q
What is the predominant mode of hepatocyte death seen in ischemic/hypoxic injury and is a significant part of oxidative stress?
A
Necrosis
8
Q
Which cells cluster at sites of hepatocyte injury and mark sites of hepatocyte necrosis?
A
Macrophages
9
Q
Councilman bodies are the apoptotic bodies associated with what disease?
A
Yellow fever
10
Q
What is the name of the apoptotic bodies seen in diseases such as acute and chronic hepatitis?
A
Acidophil bodies –> deeply eosinophilic staining
11
Q
Is stem cell replenishment a significant part of parenchymal repair during hepatocyte regeneration?
A
- NO
- Hepatocytes are almost stem-cell like in their ability to continue to replicate even in the setting of years of chronic injury
12
Q
Eventually, in chronic disease the hepatocytes reach replicative capacity (senesence) and stem cell activation occurs in the form of which reaction?
A
Ductular reactions
13
Q
What is the principal liver cell type involved in scar deposition?
A
Hepatic stellate cell
14
Q
The expression of which receptor by hepatic stellate cells is one of the initial changes during their activation into myofibroblasts?
A
PDGFR-β
15
Q
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?
A
Fibrous septa
16
Q
Stellate cells transform into myofibroblasts that when stimulated by ________ can contract
A
Endothelin-1 (ET-1)
17
Q
Chemotaxis of activated stellate cells to areas of injury are promoted by which factors?
A
- PDGF
- Monocyte chemotactic protein-1 (MCP-1)
18
Q
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?
A
- Stellate cells stop being activated
- Scars condense –> become more dense and thin
- Metalloproteinases produced by hepatocytes break the scar apart
19
Q
Acute liver failure (aka fulminant liver failure) is defined as occuring within what time period?
Associated disorders?
Pre-existing liver dysf.?
A
- Occurs within 26 weeks (6 months) of the initial liver injury
- Associated w/ encephalopathy and coagulopathy
- Absence of pre-existing liver disease
20
Q
Acute live failure is caused by what type of tisuse injury?
A
Massive hepatic necrosis
21
Q
What is the major cause of acute liver failure in the US?
What accounts for the rest of cases?
A
- Accidental or deliberate OD of Acetaminophen (major cause)
- Autoimmune hepatitis
- Other drugs/toxins
- Acute hepatitis A and B infections
22
Q
With acetaminophen toxicity, how quicly does the liver failure occur?
A
Within one week of the onset of sx’s
23
Q
In chronic inflammation which inflammatory cytokines are produced which act as stimuli for Stellate Cell activation?
A
- TNF
- Lymphotoxin
- IL-1β
24
Q
What % of hepatic functional capacity must be lost before hepatic failure ensues?
A
80-90%
25
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
26
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)
27
Which 3 viruses are most often the cause of fulminant liver failure in the setting of immunodeficiency?
- CMV
- Herpes simplex
- Adenovirus
28
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**
29
Hepatic encephalopathy seen in acute liver failue is due to elevated serum levels of?
Ammonia
30
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**
31
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**
32
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**
33
Diffuse transformation of entire liver into **regenerative parenchymal NODULES surrounded by fibrous bands** and variable degress of vascular (often portosystemic) shunting describes what?
Cirrhosis
34
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)\*
35
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**
36
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**
37
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!
38
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!
39
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**
40
What are 4 of the **most clinically significant findings** of portal HTN in the setting of cirrhosis?
1. Hepatic encephalopathy
2. Esophageal varices
3. Splenomegaly
4. Ascites
41
What is the dominant intrahepatic cause of portal HTN?
Cirrhosis
42
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
43
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**
44
What are the 3 mechanism which account for the pathogenesis of ascites?
1. **Sinusoidal HTN** promoted by **hypoalbuminemia**
2. **Percolation of hepatic lymph** into the **peritoneal cavity**
3. **Splanchnic vasodilation** and **hyperdynamic circulation**
45
What is responsible for massive hematemesis and death in pts with advanced cirrhosis of the liver?
Esophageal varices
46
Massive splenomegaly associated w/ portal HTN may secondarily induce what hematologic abnormalities?
- Thrombocytopenia --\> **low platelet count**
- Pancytopenia --\> **low red and white cells + platelets**
47
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)
48
Pts experiencing Hepatopulmonary Syndrome will have what symptom?
Dyspnea **exacerbated** in an **upright position**
\*Poorer prognosis
49
What are the 2 most common clinical manifestations of Portopulmonary HTN?
1) Dyspnea **on exertion**
2) **Clubbing** of the **fingers**
50
Which viral hepatitis does **NOT** cause chronic hepatitis or a carrier state?
Hepatitis **A**
51
Which family does Hep A belong to?
DNA or RNA virus?
Enveloped or non-enveloped?
- **Picornavirus** family
- small, **nonenveloped**, **(+)-strand RNA virus**
52
How is Hep A typically spread?
- Ingestion of contaminated food/water
- Fecal-oral
53
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
54
Which immune cell appears to play the key role in the hepatocellular injury caused during Hep A and B infection?
**CD8+ cytotoxic** **T cells**
55
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**
56
Even in the absence of cirrhosis, **chronic infection** by which **hepatitis virus** is an important precursor for the development of **hepatocellular carcinoma**?
Hepatitis B
57
In high prevalence areas of HBV what is the major mode of transmission?
Transmission during childbirth
58
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)
59
Which virus family is HBV a part of?
Describe its morphology (RNA/DNA, envelope, shape)
- **Hepadnaviridae** fam
- **Enveloped**, PARTIALLY **double-stranded circular DNA**
60
How is the diagnosis of Hepatitis A made?
Detection of **serum IgM Abs**
61
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**
62
Which "core" protein of HBV stays within hepatocytes and participates in the assembly of complete virions?
HBcAg
63
Which mature hepatitis virus, when intact, is referred to as the "**Dane particle?**"
HBV
64
What can be used for the diagnosis of HBV infection?
- Detection of **HBsAg** or **anti-HBcAg Abs**
- **PCR** for **HBV DNA**
65
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**
66
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
67
Persistence of what viral Ag in HBV infection is an important indicator of continued **viral replication**, **infectivity**, and **probable progression** to **chronic hepatitis?**
**HBeAg**
68
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
69
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
70
What % of patients infected with HBV actually go on to harbor a chronic form of the disease?
Only **5-10%**
71
Appearance of which 3 serum markers in HBV infections indicate **active viral replication?**
- HB**e**Ag
- HBV-**DNA**
- DNA **pol**
72
Histologically what is the **diagnostic hallmark** of **chronic** Hepatitis B infection?
"**Ground-glass" hepatocytes** w/ ER swollen by HBsAg
73
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**
74
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
75
Persistent infection + chronic hepatitis are the hallmarks of which viral infection?
HCV
76
Chronic disease occurs in what % of people infected by HCV?
**80-90%**
77
How does the clinical course of acute HCV infection differ from that of HBV?
**Acute HCV** --\> often asymptomatic and much **milder** than **HBV**
78
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
79
Which testing must be performed to assess viral replication and to confirm the diagnosis of HCV infection?
**PCR** for **HCV RNA**
80
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**
81
Certain polymorphism in what gene are associated with better response to treatment of HCV infection w/ IFN-α and ribavarin?
IL-28B gene
82
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
83
Lymphoid aggregates or fully formed lymphoid follicles are commonly seen assoicated with chronic hepatits by which virus?
Hepatitis **C**
84
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
85
There is a higher rate of acute hepatic failure following co-infection by HDV and HBV in whom?
IV drug users
86
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**
87
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**
88
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**
89
A characteristic feature of HEV infection is the high mortality rate among?
Pregnant woman
90
Fulminant hepatitis (acute liver failure) is unusual, but is seen primarily with which hepatitis viruses?
- HAV
- HBV
- HDV
\*HEV in pregnant women
91
In some patients with Chronic Hepatitis the only signs are persistent elevations of?
Serum transaminases
92
Cryoglobulinemia is found in about 35% of pts with what type of hepatits infection?
Chronic hepatitis C
93
What is the leading cause of morbidity and mortality for HIV-infected patients?
Chronic **HBV** or **HBC** infection
94
What is the defining histological feature of chronic viral hepatitis?
**DENSE** mononuclear **portal** infiltration
95
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**
96
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**
97
Bile duct injury, potentially mimicing primary biliary cirrhosis is prominent in some pts with what type of viral hepatitis?
Hepatitis **C**
98
**Fatty change** of scattered hepatocytes is associated with what type of viral hepatitis?
Hepatitis **C**, particularly **genotype 3**
99
Which organisms most commonly found is SE Asia is notorious for causing a very high rate of cholangiocarcinoma?
**Liver flukes** (**trematodes**)
100
Acute inflammatory response within the intrahepatic biliary tree caused by gut/biliary tree microflora is called?
**Ascending cholangitis**
101
Which region is the highest annual incidence of Autoimmune Hepatitis seen in?
Which sex is more often affected?
- White Northern Europeans
- Females
102
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)**
103
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**
104
What is the most prominent and characteristic component of the inflammatory infiltrate associated with Autoimmune Hepatitis?
Plasma cells
105
Hepatocyte **"rosettes"** in areas of marked activity are a characteristic of which disease?
Autoimmune Hepatitis
106
Very severe hepatocyte injury with widespread confluent necrosis, but little scarring, represents which stage of Autoimmune Hepatitis?
First sign of disease = symptomatic acute hepatitis
107
In general, prognosis of Autoimmune Hepatitis is better in which age group?
Better prognosis in **adults**
108
What is the most common cause of **acute liver failure** necessitating transplantation in the US?
Acetaminophen
109
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**
110
This pattern of hepatocyte injury is characteristic of which toxicity?
- Acetaminophen toxicity
- Confluent necrosis seen in **perivenular region** (**zone 3**)
111
"Microvesicular steatosis" (diffuse small droplet fat) is a morphological finding associated with toxicity by which agent?
Which syndrome specifically?
**Aspirin** (in **Reye syndrome**)
112
Bland hepatocellular cholestasis, without inflammation, is characteristic of toxicity due to what agent?
Anabolic streroids
\*Also OC's
113
Blood-filled cavities, not lined by endothelial cells, knows as **Peliosis hepatitis** is associated with toxicitiy by which agent?
Anabolic steroids
114
Which 2 agents are associated with Hepatocellular Adenoma?
1. Oral contraceptives
2. Anabolic steroids
115
Which 2 agents are assoicated witn Angiosarcoma of the liver?
1. Thorotrast
2. Vinyl Choride
116
Which 2 agents are associated with Hepatocellular Carcinoma?
1. Alcohol
2. Thorotrast
117
Which agent is associated with Cholangiocarcinoma?
Thorotrast
118
Can Hepatic Steatosis (Fatty Liver) associated with alcohol intake be reversed?
**Completely reversible** with abstinence from alcohol
119
Alcoholic (Steato-) Hepatitis is characterized by what 3 morphological findings?
1. **Hepatocyte swelling** + **necrosis** = "**Ballooning**"
2. **Mallory-Denk bodies**: clumped, amorphous, eosinophilic material in ballooned hepatocytes
3. **Neutrophilic rxn**: accumulate around degenerating hepatocytes
120
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
121
Scarring/fibrosis seen in Alcoholic Steatofibrosis characteristically follows what type of pattern?
**Chicken wire fence** pattern
122
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**
123
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
124
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)
125
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)
126
↑ 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**
127
The most common **acquired** metabolic disorder of the liver is?
Non-alcoholic fatty liver disease (NAFLD)
128
What is the most common cause of chronic liver disease in the US?
NAFLD
129
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 **i****mpaired glucose tolerance**or**i****mpaired fasting glucose** or **i****nsulin resistance**
**_Two of:_**
- **BP \>140/90** or **Dyslipidemia** or **Central obesity** or **Microalbuminuria**
130
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**
131
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**
132
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**
133
\>90% of previously described "cryptogenic cirrhosis" (i.e., cirrhosis of unknown cause) is now thought to represent what?
**"Burned out" NAFLD**
134
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
135
What is the 2 hit model for the pathogenesis of NAFLD and how do insulin resistance and oxidative injury play a role?
1. **Insulin resistance** --\> **hepatic steatosis**
2. Hepatocellular oxidative injury ---\> liver cell **necrosis** and **inflammatory rxns** to it
136
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**
137
Due to the association of NASH w/ metabolic syndrome what is a frequent cause of death in these patients?
Cardiovascular disease
138
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
139
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**)
140
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**
141
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**
142
The adult form of hemochromatosis is almost always causes by a mutation in which gene?
Located on what chromosome?
- ***HFE***
- Chromosome **6**
143
The most common *HFE* mutation is a substitution of what AA's at which AA?
**Cysteine-to-tyrosine** substitution at **AA 282** --\> **C282Y**
144
The C282Y mutation of the HFE gene causing hemochromatosis is largely confined to which population of people?
**White** populations of **European** origin
145
Is the direct toxic injury produced by iron on hepatocytes and other cells reversible?
**Yes**, if removed before they are fatally injured
146
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
147
What is seen morphologically in the heart of severe hemochromatosis?
- Often **enlarged**
- Hemosiderin in myocardial fibers --\> **brown myocardium**
148
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
149
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)
150
Derangement of the HPA axis associated with severe hemochromatosis may cause?
**Testes** to be **small** and **atrophic**
151
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)
152
Patients with what metabolic liver disease have a **200-fold** greater risk of developing hepatocellular carcinoma?
Hemochromatosis
153
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
154
Screening of whom for hemachromatosis is important?
Family members of **probands** (the 1st person in a family to have the disease)
155
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**
156
Which treatment is utilized to deplete tissue iron stores in pts with hemochromatosis and generally leads to a normal life expectancy?
Phlebotomy
157
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**
158
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***
159
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
160
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
161
Excess copper in Wilson Disease can often be demonstrated by using what special stains?
- **Rhodamine** stain for copper
- **Orcein** stain for copper-associated protein
162
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**)
163
Toxic injury to the brain associated with Wilson Disease primarily affects which area?
**Basal ganglia,** primarily the **putamen,** which shows **atrophy** and even **cavitation**
164
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**
165
Due to the toxicity of copper to red cell membranes what complication may arise in Wilson Disease?
Hemolytic anemia
166
What is the inheritance pattern of α1-antitrypsin deficiency?
Which chromosome is the mutated gene located on?
- Autosomal **recessive**
- Chromosome **14**
167
What is the normal function of α1-antitrypsin?
Normally acts on?
**Inhibition** of **proteases:**
- ***N****eutrophil elastase***
***- Cathepsin G***
***- Proteinase 3***
168
α1-antitrypsin deficiency leads to the development of what 2 main disorders?
- Pulmonary emphysema
- Liver disease
169
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
170
What is the most commonly diagnosed inherited hepatic disorder in infants and children?
α1-antitrypsin deficiency
171
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**
172
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**
173
Which % of adults with the PiZZ genotype will develop hepatocellular carcinoma?
**2-3%**; usually, but not always, in the setting of **cirrhosis**
174
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
