House MD Guide :: Blogs :: Differential Diagnosis:
A Medical Guide to House
A Simple Case of Vampirism
"Watson, if it should ever strike you that I am getting a little over-confident in my powers, or giving less pains to a case than it deserves, kindly whisper 'Norbury' in my ear, and I shall be infinitely obliged to you." - Sherlock Holmes, The Yellow Face
Alice is a 6-year-old girl who experiences problems with vision on a carnival ride and ends up in the hospital with abdominal pain, apparently due to pancreatitis. She has a low-grade fever and mild anemia. Her bile duct is dilated on a CT scan, indicative of stones in the bile duct (choledocholithiasis
). The stones weren't visualized, so House states that the stones likely passed already and recommends an ultrasound to see if there are any stones left in the gallbladder. Gallstones are visualized in the gallbladder, and House recommends removal of the gallbladder to figure out what the cause is. After some court drama, the patient has her gallbladder removed (cholecystectomy
). Following the surgery, Alice complains about pain from her stitches and Foreman notes a bright red vesicular rash with areas of denuded skin. She has no history of allergies. The stones are noted to contain calcium and bilirubin with a pigmented appearance. Because the patient presented with a low-grade fever and mild anemia, House suggests a bacterial infection. Foreman argues that bacterial infections do not cause a vesicular rash. House suggests a scratch test to rule out allergies. The scratch test is positive for all antigens. House is still convinced that the cause is bacterial and gives the patient a peanut butter sandwich to prove that she is not allergic to everything. House wants to start broad-spectrum antibiotics, but because of some more court drama, Cuddy is appointed guardian of the child and decides to give metronidazole
instead. The patient becomes hypertensive and tachycardic. After she is stabilized, Alice's father takes her and leaves the hospital but returns promptly when the Alice becomes stiff. House suspects that the patient's babysitter gave her an aspirrin (leading to Reye's syndrome
) and tells Cuddy to put the patient on charcoal hemoperfusion. In the middle of the procedure, Alice starts experiencing extreme pain and paralysis in her left hand. She starts to become hyperthermic and thrombocytopenic. The vesicular rash spreads to her left arm. Her fever increases to 103. House suggests that the patient may have varicella based on its appearance but this doesn't fit because the patient has paralysis and no itching. Cameron suggests Rocky Mountain Spotted Fever
. House says to start the patient on chloramphenicol for Rocky Mountain Spotted Fever. The rash spreads throughout her arms and legs, so House diagnoses her with necrotizing fasciitis
and recommends bilateral arm and leg amputation. As the patient is on the operating table, Chase has a realization that the patient may have erythropoetic protoporphyria
and runs down to tell House. Someone calls the surgeon and the surgery is cancelled.The diagnosis:
Erythropoetic protoporphyriaWorking backwards:
When Chase made the diagnosis of erythropoetic protoporphyria, he did so working on the assumption that the patient's allergic tendencies could be attributed to light exposure. Based on the Harrison's textbook, the first two lab studies to check when a patient is sensitive to light is a plasma porphyrin (to rule out porphyrias) and an ANA/Ro/La (to rule out lupus and other similar autoimmune processes). Even though Chase didn't order either of these studies, it makes sense that he presumed that one of these two diseases was leading to the patient's symptoms once he made the connection to the light. Had he ordered the tests, he would have found increased levels of plasma porphyrin. Some of the common porphyrias are porphyria cutanea tarda (#1), erythropotoetic protoporphyria (#2), and acute intermittent porphyria. If you tested the urine for porphyrins, porphyria cutanea tarda would show a normal porphobilinogen level and an increased uroporphyrin and 7-carboxylate level; erythropoetic protoporphyria would show normal porphyrin and porphyrin precursor levels; and acute intermittent porphyria would show increased levels of porphobilinogen.Loose ends:Q:
If the disease is genetic, why don't either of Alice's parents show symptoms of the disease?A:
The disease is autosomal dominant, which means that even one copy of the gene should give you symptoms. However, some people with only one copy of the gene have been noted to have no symptoms, so there is a documented variation in the severity of the disease.Q:
Why was a diagnosis of pancreatitis thrown around early in the episode after the patient presented with abdominal pain?A:
Generally, when a doctor says that a patient likely has pancreatitis, he or she does so based on a blood sample that shows increased levels of amylase and lipase. Because pancreases make amylase and lipase to help digest food, damage to the pancreas breaks down individual pancreatic cells and releases these enzymes into the bloodstream, thereby elevating their levels in the blood. A CT scan could then be performed 48 hours after the onset of symptoms, with the goal to try to visualize some kind of fluid or cyst in the pancreas. I'm assuming then that this diagnosis was made because Alice was experiencing excruciating abdominal pain and had increased levels of amylase and lipase. Erythropoetic protoporphyrias are actually associated with gallstones (composed of insoluble crystalline protoporphyrin), which could have lodged in the common bile duct (like the one in the picture), creating a blockage of the main pancreatic duct and increasing the risk for pancreatitis.Q:
When Alice first developed a rash on her arm, why was it attributed to thrombocytopenia?A:
Thrombocytopenia is a low level of platelets, which can result in a petechial rash. From way up in the surgery viewing booth, it's possible that the patient's rash looked petechial in nature (like in the picture). I can't really think of a better explanation because I don't think a blood test was every run to confirm or reject this idea. Petechiae generally appear as small little dots.Q:
What things besides pancreatitis (and other anatomical diseases like appendicitis) can lead to abdominal pain, like the kind that Alice had?A:
There's a mnemonic I use from the Saint-Frances Guide to Inpatient Medicine
to remember all the non-typical causes of abdominal pain.P
y BAD LUNCH
lack widow spider biteA
ddison's disease, A
Did vampires suffer from porphyria?A:
There is some thought that legends of vampires were based off of people who suffered from porphyria. Porphyria causes severe rashes when a person is exposed to sunlight, and one way to treat porphyrias is to transfuse blood products. Centuries ago when blood products weren't readily available, it would be theoretically possible to receive blood by drinking it straight from a victim's neck veins. Here's an interesting article
that goes more into depth on the topic.
A Case of the Itchy Feet
Jack is an 18-year-old boy who presents to the hospital after experiencing a heart attack and massive vomiting. During the work-up, he tests positive for a number of bacteria.The Diagnosis:
Chronic granulomatous disease (CGD)Working Backwards:
In this case, the diagnosis wasn't impossible to make. Fairly early in the episode, House and his underlings run into an interesting finding: positive tests for Hepatitis A, syphilis, Eikenella, and botulism.
"So, we knocked down one infection and three more pop up? I think this game is rigged." - House
Well actually, any disease that targets the immune system can make you prone to recurrent infections. A relatively common disease that is often tested for in patients with unusual or widespread infections is Human Immunodeficiency Virus (HIV). But since when do House's patients come in with relatively common conditions? Seeing as how 2 of the last 3 House diagnoses (Episodes 305 and 307) have been genetic diseases, it's not a huge leap of the imagination that the writers of House would pick another hereditary condition for this episode. In all fairness, medical students acquire a knee-jerk reaction to thinking about hereditary immune deficiencies when the words "recurrent infections" show up in questions, so the final diagnosis was in some ways not entirely unexpected. However, chronic granulomatous disease isn't the only disease that fits into the category of genetic immune deficiencies, and here's where the medicine becomes interesting.The Medicine:
In order to understand how House arrived at the diagnosis of chronic granulomatous disease (CGD), you need to know a little bit about how the normal immune system works. The immune system is made up white blood cells, which are often fancily referred to as leukocytes or WBCs. There are five major types of white blood cells that make up the immune system: lymphocytes, monocytes (aka macrophages), basophils, neutrophils, and eosinophils.
Lymphocytes come in three flavors, B-cells, T-cells, and Natural Killer (NK) cells. B-cells can become plasma cells and produce antibodies. T-cells exist in 2 forms, helper T-cells and killer T-cells. Helper T-cells are a bit like antibodies and help tag bacteria for destruction. Killer T-cells and NK cells do exactly what it sounds like they do -- they kill bacteria. Monocytes are big and slow Pacman-like cells that eat other cells whole. It can take 3-5 days for these bad boys to arrive on the scene, and so the immune system has neutrophils, which are smaller and stealthier. Basophils are basically wimps. Eosinophils fight crime in the form of parasitic infections.
So where does CGD fit into all this? Well, CGD affects the ability of neutrophils to eat bacteria. Just before healthy neutrophils eat a cell, they like to spray it with it with detergent (Picture bleach being splattered onto a bacterium and the bacterium writhing in pain). Why the need for detergent? Well, as sad as it is, neutrophils lack teeth and so they need a way to chew up the bacteria so that they can swallow it (apparently, neutrophils have throats and stomachs). They take electrons from a compound known as NADPH (nicotinamide adenine dinucleotide phosphate-oxidase) and transfer it onto oxygen to make superoxide, which is toxic to cells. In CGD, the enzyme that makes superoxide is broken, so the neutrophils suck at their jobs. Infections run rampant.
Not all infections run rampant though. This is the basis for the kooky "test" that House runs by injecting Jack with all those different bacteria. Interestingly, bacteria are neutrophil-wannabes in one way. Bacteria also have an enzyme that makes superoxide. Instead of using superoxide to kill bacterial cells, bacteria release superoxide to kill human cells. Sometimes, with all the superoxide flying around, bacteria can get caught in the crossfire and die off. Certain bacteria have an enzyme (called catalase) that can disarm superoxide, which prevents them from being killed by the crossfire. Bacteria (and fungi) that have catalase include Staphylococcus, Aspergillus, and Gram-negative rods (which includes Serratia and sometimes Eikenella). This is why when House injected all those different organisms into Jack, Serratia won out. Syphilis (caused by the bacterium Treponema pallidum) and botulism (caused by Clostridium botulinum) generally do not have catalase, although this doesn't exlude their ability to infect Jack, given that he has other catalase-containing bacteria to help out.
One final point: CGD is usually passed from one generation of a family to the next on patients' X-chromosomes, which means that males are predisposed to manifesting the condition. Since neither of Jack's parents were seemingly affected, his mom was the likely carrier (since her other normal X-chromosome made up the losses of the mutated one).What's the deal with the itchy feet?
For some reason, House was really caught up on Jack's itchy feet. Apparently, according to Harrison's (a big thick textbook), CGD can be associated with seborrheic dermatitis, which could in theory cause itching. I actually got thrown off by this whole itching symptom because one of the immune deficiencies that is classically associated with itching (in the form of eczema) is Wiskott-Aldrich syndrome. Lastly, the itching could have been due to a fungal infection, seeing as how Jack's immune system isn't so great. Most likely, Cameron was right when she said that he got it from wearing sweaty socks while running around at work. That's how my feet feel when I'm post-call.
Like Father, Like Son
Kyle is a man in his 20s with a history of mild seizures who presents with intermittent akinotopsia (loss of motion vision) and generalized myoclonic seizure after exposure to flashing lights. He says that he has gone through an extensive work-up for seizures which was unremarkable. During questioning, an underlying history of alcohol abuse is uncovered, and Kyle's becomes obtunded from liver failure.
"Ragged red fiber.. it's an inherited condition. Dropping things, muscle weakness, poor night vision... these people seem uncoordinated, accident-prone, careless... it's transmitted in mitochondrial DNA so it only passes through the mother. Your wife's family weren't drunks. They were sick."
I'm not going to criticize the randomness of this diagnosis. Why? Because this season, that's become the norm with all of House's diagnoses. You might even argue that there's no proof that House is even right in this case because no one ever does run the DNA test for it. If you're willing just accept that House is right and to work backwards, join in on the ride. If you're frustrated with House's diagnosis, go to the last two paragraphs of this post. Oh, did I say I wouldn't criticize House? I lied. Everybody lies.
Now read on.
"Ragged red fiber disease" was a name used to describe a set of mitochondrial myopathies ("myopathy" = muscle problem) in 1972 because muscle fibers with enough abnormal mitochondria were colored red when viewed under a microscope after modified trichrome staining. Each human cell is made up of a number of parts. Mitochondria are one of those parts. What makes mitochondria different from every other part of the cell is that evolutionarily, it's thought that mitochondria were once indendepent organisms. Why? Well, for one, they actually have their own DNA separate from the DNA found in human cells.
Secondly, they have two membrane layers surrounding them, one thought to be derived from the original organism and one from the human cell, thereby forming a nice friendly "symbiotic" relationship. Seeing as how every single human cell have mitochondria and mitochondria serve as the main energy powerhouses of the cell, if mitochondrial DNA gets messed up, it means that bad, bad things can happen. Also, because sperm mitochondria are destroyed when a sperm first meets an egg, the vast majority of an embyro's mitochondria come from the egg, and thus from the mother. In other words, if a woman has a mitochondrial disease, all her kids will have that disease.
As you can imagine, more than one thing can go wrong with mitochondrial DNA. For that reason, the word "ragged red fiber disease" actually refers to a whole group of diseases. The single most common sign of all of the mitochondrial myopathies is the progressive weakening in the ability to move your eyes without
seeing double. I guess if you really stretch it, this could manifest as the loss of motion vision, just like Kyle had. Fine. So far so good. Now we need to account for the seizures. If we're going to stick with the "ragged red fiber disease" theory, there are two types of mitochondrial myopathies that initially present with seizures: myoclonic epilepsy with ragged red fibers (MERRF) and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). At one point, Kyle's father refers to him dropping things. Because MERRF is classically associated with limb-girdle weakness, we'll assume that Kyle has MERRF. Kyle's liver failure and cardiomyopathy are both commonly caused by alcohol abuse, so we'll consider these things accounted for.
In one scene, when Wilson, House, and Gabriel (Kyle's father) are in the hotel room, Gabriel says "Wilson, toss me a soda." Wilson throws it across the room, it hits Gabriel's hand, and it falls to the ground. House looks at Gabriel with inquisitive eyes with that "I just made the diagnosis" look. It appears as though Gabriel and Kyle both have a problem with seeing moving objects. In fact, early in the episode, House says that Kyle and Gabriel have similar EEG findings. If ragged red fiber disease is inherited from a person's mother, why would Kyle's dad have signs of the same disease that Kyle has?
Kyle's father Gabriel must have slept with his own mother to create Kyle. Therefore, it's actually Gabriel and Kyle who have ragged red fiber disease. This means that once the mother's side of the family found out who Kyle's real mother was, they became a bunch of drunks.
Clinic Patients: Santa Claus
House: Let me guess... inflammatory bowel.
Santa: Wow, yeah. Is it that bad?
House: Yes. It's also written on your chart. Bloody diarrhea, gas, pain... took sulfasalazine, but it didn't work -
Santa: No, then I -
House: Next tried steroid enemas, oral corticosteroids, 5-ASAs, 6-mercaptopurine... I'm impressed.
Santa: By my medical history?
House: By how well your last doctor charted.
Santa: It's one thing to have to go to the bathroom every hour, but when the kids sit on my lap, it's... The store sent me home, they're gonna fire me. Can't you put me back on 5-ASA? Maybe it'll work this time?
House: Not likely. I'm giving you a prescription. It's cheap, which is good because your insurance company won't pay for it. [He gives Santa a prescription, who puts on his glasses to read it.]
Santa: [tries to read House's writing] Cojorius?
House: Cigarettes. One twice a day, no more, no less. Studies have shown that cigarette smoking is one of the most effective ways to control inflammatory bowel, plus it's been established that you look 30% cooler.
Santa: Are you kidding me?
House: About the looking cooler, yeah. The rest is true.
Santa: Isn't it addictive and dangerous?
House: Pretty much all the drugs I prescribe are addictive and dangerous. The difference with this one is that it's completely legal. [He turns to leave.] Merry Christmas.
What does the evidence say?
"Certain lifestyle factors also play a role in inflammatory bowel disease. Smoking may be associated with an increased risk of Crohn's disease, especially postoperative recurrence. In contrast, smoking is associated with a decreased risk of ulcerative colitis, and nicotine patches apparently have some benefit in patients with active disease. However, nicotine patches do not help maintain remission of ulcerative colitis." -- American Family Physician
"Ulcerative colitis is largely a disease of nonsmokers, and patients with ulcerative colitis who are exsmokers have usually acquired the disease within a few years after they stopped smoking. Patients who smoke intermittently often experience improvement in their colitis symptoms during the periods when they are smoking. Treatment with transdermal nicotine patches and mesalamine (5-aminosalicylic acid) has a beneficial effect on active colitis." -- Thomas GA, Rhodes J, Mani V, Williams GT, Newcombe RG, Russell MA, et al. Transdermal nicotine as maintenance therapy for ulcerative colitis. N Engl J Med 1995;332:988-92.
What does this mean?
If Santa were a former smoker, this advice may be medically relevant specifically in terms of the ulcerative colitis. As a general rule though, most medications don't cause 85% of all lung cancers. Nicotine patches, however, don't cause lung cancer and can be beneficial for active colitis. And if Santa really was a heavy smoker, nicotine patches might even be cheaper!