USMLE Insider Prep Course

Which of the following patients should undergo prophylactic gonadectomy: a patient with 45,X; a patient with 46, XX type of pure gonadal dysgenesis; or a patient with 46,XY type of pure gonadal dysgenesis?

When confronted with this question on the test, it is important to recognize that the risk of gonadal malignancy is increased when a Y chromosome is present in the karyotype. Neither Turner syndrome nor the 46, XX type of pure gonadal dysgenesis appears to be associated with an increased risk of gonadal malignancy unless a Y chromosome is present in the mosaic forms.

Prophylactic gonadectomy is advised in the Y mosaic Turner syndrome because the risk of gonadoblastoma is estimated to be 12%. The 46,XY type of pure gonadal dysgenesis possesses a different problem because the bilateral streak go**ds carry a significant potential for malignancy. Nearly one third of patients develop a dysgerminoma or gonadoblastoma; therefore, gonadectomy becomes important as soon as the diagnosis is recognized followed by cyclic hormone replacement with estrogen and progestins. In addition to gonadoblastomas, seminomas, and embryonal cell carcinomas may develop. Early gonadectomy is recommended because tumors may arise in the first decade.

At USMLE Insider, we prep you comprehensively so that you can count on getting at least 90% of the questions on your test date from our course materials.

Which USMLE-favorite disease may be associated with a quintuple cadence on auscultation? Ebstein’s anomaly of the tricuspid valve, which results from downward displacement of the tricuspid valve towards the apex of the right ventricle.

This displacement causes “atrialization” of a portion of the morphologic right ventricle which is then contiguous with the right atrium leading to right atrial hypertrophy and right ventricular hypoplasia.

A quadruple rhythm (S3 and S4) associated with the systolic murmur of tricuspid regurgitation and a mid-diastolic murmur at the lower left sternal border suggests the diagnosis. The presence of right atrial hypertrophy and right ventricular conduction defects confirms the diagnosis.

50% of patients with Ebstein’s anomaly have the electrophysiological abnormality, Wolff-Parkinson-White syndrome, secondary to the atrialized right ventricular tissue. About 50% of individuals with Ebstein anomaly have an associated shunt between the right and left atria, either an atrial septal defect (ASD) or a patent foramen ovale.

A quintuple cadence on auscultation may be characteristic because the S1 is split and the usual presence of an ASD causes wide splitting of the S2. These sounds together with the S3 and S4 produce a quintuple cadence on auscultation.

Imagine an elderly patient with lipoproteinemia who has been stabilized on simvastatin for years. Let’s say this patient also has rheumatoid arthritis that has failed to respond to NSAIDs. One week after receiving a single 200 mg subcutaneous dose of a drug for arthritis, her plasma concentration of simvastatin is found to be markedly decreased. Which anti-arthritis medication could have caused this phenomenon?

You already know that simvastatin is a substrate of CYP450 3A4 and OATP 1B1. What may be difficult to understand is that plasma concentrations of drugs that are CYP450 substrates may decrease following the initiation of interleukin (IL) inhibitors, tumor necrosis factor (TNF) blockers, or interferon (IFN) inhibitors in patients with chronic inflammatory diseases, such as rheumatoid arthritis.

Normally, the formation of hepatic CYP450 enzymes is down-regulated during infection and chronic inflammation by increased levels of certain cytokines (e.g., interleukins-1, -6, and -10; tumor necrosis factor alpha; interferons). Consequently, treatment targeting these cytokines may restore or normalize CYP450 enzyme levels resulting in increased metabolism of these drugs.

Simvastatin systemic exposure is decreased by 45% by a single dose of sarilumab, an IL-6 inhibitor, in rheumatoid arthritis patients.

In fact, tocilizumab, another IL-6 inhibitor, has been found to impact expression of various CYP enzymes including CYP450 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4.

Because no role for other interleukins such as IL-12, IL-17A, or IL-23 in the regulation of CYP450 enzymes has been established, risankizumab and tildrakizumab, both IL-23 antagonists, should not be answers to pick on the USMLE regarding this specific concept. This does not mean that risankizumab and tildrakizumab won’t be tested in other capacities; there are always questions testing their dermatologic applications and immunophysiologic mechanisms. But with regards to USMLE questions relating to hepatic microsomal enzymes and drug metabolism, always go with IL-1, IL-6, and IL-10 modulators (No IL-10 modulators are clinically available currently, so that leaves only IL-6 and IL-10).

Now, besides sarilumab and tocilizumab, which other IL-6 modulators can you name?

We’ve been helping physicians pass their USMLE since 2005. Our courses aren’t just updated to the newest standards—they’re also based on decades of experience, which means we know what it takes for our students to succeed. Join us for our July 2023 class.